Browsing by Subject "ALPHA"

Sort by: Order: Results:

Now showing items 1-20 of 22
  • Laakasuo, Michael; Sundvall, Jukka (2016)
    Utilitarian versus deontological inclinations have been studied extensively in the field of moral psychology. However, the field has been lacking a thorough psychometric evaluation of the most commonly used measures. In this paper, we examine the factorial structure of an often used set of 12 moral dilemmas purportedly measuring utilitarian/deontological moral inclinations. We ran three different studies (and a pilot) to investigate the issue. In Study 1, we used standard Exploratory Factor Analysis and Schmid-Leimann (g factor) analysis; results of which informed the a priori single-factor model for our second study. Results of Confirmatory Factor Analysis in Study 2 were replicated in Study 3. Finally, we ran a weak invariance analysis between the models of Study 2 and 3, concluding that there is no significant difference between factor loading in these studies. We find reason to support a single-factor model of utilitarian/deontological inclinations. In addition, certain dilemmas have consistent error covariance, suggesting that this should be taken into consideration in future studies. In conclusion, three studies, pilot and an invariance analysis, systematically suggest the following. (1) No item needs to be dropped from the scale. (2) There is a unidimensional structure for utilitarian/deontological preferences behind the most often used dilemmas in moral psychology, suggesting a single latent cognitive mechanism. (3) The most common set of dilemmas in moral psychology can be successfully used as a unidimensional measure of utilitarian/deontological moral inclinations, but would benefit from using weighted averages over simple averages. (4) Consideration should be given to dilemmas describing infants.
  • The Milieu Intérieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank Investigators; COVID Human Genetic Effort; CONSTANCES cohort; 3C-Dijon Study; Cerba HealthCare; Etablissement du Sang study group; HGID Lab; COVID Clinicians; COVID-STORM Clinicians; NIAID Immune Response to COVID Group; NH-COVAIR Study Group; Danish CHGE; Danish Blood Donor Study; St. James’s Hospital SARS CoV2 Interest group; French COVID Cohort Study Group; Imagine COVID Group; Bastard, Paul; Gervais, Adrian; Le Voyer, Tom; Seppänen, Mikko R. J. (2021)
    Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-alpha and/or IFN-omega are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-alpha and/or IFN-omega (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-beta. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-alpha and/or IFN-omega are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-beta do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases.
  • Karvinen, Sira; Fachada, Vasco; Sahinaho, Ulla-Maria; Pekkala, Satu; Lautaoja, Juulia H.; Mäntyselkä, Sakari; Permi, Perttu; Hulmi, Juha J.; Silvennoinen, Mika; Kainulainen, Heikki (2022)
    Impaired lipid metabolism is a common risk factor underlying several metabolic diseases such as metabolic syndrome and type 2 diabetes. Branched-chain amino acids (BCAAs) that include valine, leucine and isoleucine have been proven to share a role in lipid metabolism and hence in maintaining metabolic health. We have previously introduced a hypothesis suggesting that BCAA degradation mechanistically connects to lipid oxidation and storage in skeletal muscle. To test our hypothesis, the present study examined the effects of BCAA deprivation and supplementation on lipid oxidation, lipogenesis and lipid droplet characteristics in murine C2C12 myotubes. In addition, the role of myotube contractions on cell metabolism was studied by utilizing in vitro skeletal-muscle-specific exercise-like electrical pulse stimulation (EPS). Our results showed that the deprivation of BCAAs decreased both lipid oxidation and lipogenesis in C2C12 myotubes. BCAA deprivation further diminished the number of lipid droplets in the EPS-treated myotubes. EPS decreased lipid oxidation especially when combined with high BCAA supplementation. Similar to BCAA deprivation, high BCAA supplementation also decreased lipid oxidation. The present results highlight the role of an adequate level of BCAAs in healthy lipid metabolism.
  • Raivola, Juuli; Haikarainen, Teemu; Silvennoinen, Olli (2020)
    The Janus kinase-signal transducer and activator of transcription protein (JAK-STAT) pathway mediates essential biological functions from immune responses to haematopoiesis. Deregulated JAK-STAT signaling causes myeloproliferative neoplasms, leukaemia, and lymphomas, as well as autoimmune diseases. Thereby JAKs have gained significant relevance as therapeutic targets. However, there is still a clinical need for better JAK inhibitors and novel strategies targeting regions outside the conserved kinase domain have gained interest. In-depth knowledge about the molecular details of JAK activation is required. For example, whether the function and regulation between receptors is conserved remains an open question. We used JAK-deficient cell-lines and structure-based mutagenesis to study the function of JAK1 and its pseudokinase domain (JH2) in cytokine signaling pathways that employ JAK1 with different JAK heterodimerization partner. In interleukin-2 (IL-2)-induced STAT5 activation JAK1 was dominant over JAK3 but in interferon-gamma (IFN gamma) and interferon-alpha (IFN alpha) signaling both JAK1 and heteromeric partner JAK2 or TYK2 were both indispensable for STAT1 activation. Moreover, IL-2 signaling was strictly dependent on both JAK1 JH1 and JH2 but in IFN gamma signaling JAK1 JH2 rather than kinase activity was required for STAT1 activation. To investigate the regulatory function, we focused on two allosteric regions in JAK1 JH2, the ATP-binding pocket and the alpha C-helix. Mutating L633 at the alpha C reduced basal and cytokine induced activation of STAT in both JAK1 wild-type (WT) and constitutively activated mutant backgrounds. Moreover, biochemical characterization and comparison of JH2s let us depict differences in the JH2 ATP-binding and strengthen the hypothesis that de-stabilization of the domain disturbs the regulatory JH1-JH2 interaction. Collectively, our results bring mechanistic understanding about the function of JAK1 in different receptor complexes that likely have relevance for the design of specific JAK modulators.
  • Koivisto, Elina; Acosta, Alicia Jurado; Moilanen, Anne-Mari; Tokola, Heikki; Aro, Jani; Pennanen, Harri; Sakkinen, Hanna; Kaikkonen, Leena; Ruskoaho, Heikki; Rysa, Jaana (2014)
  • Aspatwar, Ashok; Barker, Harlan; Aisala, Heidi; Zueva, Ksenia; Kuuslahti, Marianne; Tolvanen, Martti; Primmer, Craig R.; Lumme, Jaakko; Bonardi, Alessandro; Tripathi, Amit; Parkkila, Seppo; Supuran, Claudiu T. (2022)
    A beta-class carbonic anhydrase (CA, EC 4.2.1.1) was cloned from the genome of the Monogenean platyhelminth Gyrodactylus salaris, a parasite of Atlantic salmon. The new enzyme, GsaCA beta has a significant catalytic activity for the physiological reaction, CO2 + H2O (sic) HCO3- + H+ with a k(cat) of 1.1 x 10(5) s(-1) and a k(cat)/K-m of 7.58 x 10(6) M-1 x s(-1). This activity was inhibited by acetazolamide (K-I of 0.46 mu M), a sulphonamide in clinical use, as well as by selected inorganic anions and small molecules. Most tested anions inhibited GsaCA beta at millimolar concentrations, but sulfamide (K-I of 81 mu M), N,N-diethyldithiocarbamate (K-I of 67 mu M) and sulphamic acid (K-I of 6.2 mu M) showed a rather efficient inhibitory action. There are currently very few non-toxic agents effective in combating this parasite. GsaCA beta is subsequently proposed as a new drug target for which effective inhibitors can be designed.
  • Grabon, Aby; Orlowski, Adam; Tripathi, Ashutosh; Vuorio, Joni; Javanainen, Matti; Rog, Tomasz; Lönnfors, Max; McDermott, Mark I.; Siebert, Garland; Somerharju, Pentti; Vattulainen, Ilpo; Bankaitis, Vytas A. (2017)
    Phosphatidylinositol-transfer proteins (PITPs) regulate phosphoinositide signaling in eukaryotic cells. The defining feature of PITPs is their ability to exchange phosphatidylinositol (PtdIns) molecules between membranes, and this property is central to PITP-mediated regulation of lipid signaling. However, the details of the PITP-mediated lipid exchange cycle remain entirely obscure. Here, all-atom molecular dynamics simulations of the mammalian StART-like PtdIns/phosphatidylcholine (PtdCho) transfer protein PITP alpha, both on membrane bilayers and in solvated systems, informed downstream biochemical analyses that tested key aspects of the hypotheses generated by the molecular dynamics simulations. These studies provided five key insights into the PITP alpha lipid exchange cycle: (i) interaction of PITP alpha with the membrane is spontaneous and mediated by four specific protein substructures; (ii) the ability of PITP alpha to initiate closure around the PtdCho ligand is accompanied by loss of flexibility of two helix/loop regions, as well as of the C-terminal helix; (iii) the energy barrier of phospholipid extraction from the membrane is lowered by a network of hydrogen bonds between the lipid molecule and PITP alpha; (iv) the trajectory of PtdIns or PtdCho into and through the lipidbinding pocket is chaperoned by sets of PITP alpha residues conserved throughout the StART-like PITP family; and (v) conformational transitions in the C-terminal helix have specific functional involvements in PtdIns transfer activity. Taken together, these findings provide the first mechanistic description of key aspects of the PITP alpha PtdIns/PtdCho exchange cycle and offer a rationale for the high conservation of particular sets of residues across evolutionarily distant members of the metazoan StART-like PITP family.
  • Warnecke, Jörn; Käpylä, Petri J.; Mantere, Maarit J.; Brandenburg, Axel (2012)
  • Chen, Yan; Ma, Yuan; Feng, Jin Jin; Wang, Yi He; Li, Tian Fang; Nurmi, Katariina; Eklund, Kari K.; Wen, Jian Guo (2021)
    NLRP3 inflammasome has been implicated in impaired post-injury muscle healing and in muscle atrophy. Histamine receptors play an important role in inflammation, but the role of histamine H-3 receptor (H3R) in myocyte regeneration and in the regulation of NLRP3 inflammasome is not known. We studied the effects of H3R signaling on C2C12 myocyte viability, apoptosis, and tumor necrosis factor alpha (TNF alpha)-induced NLRP3 inflammasome activation during striated myogenic differentiation at three time points (days 0, 3, and 6). Expression of Nlrp3, interleukin-1 beta (IL-1 beta), and myogenesis markers were determined. TNF alpha reduced overall viability of C2C12 cells, and exposure to TNF alpha induced apoptosis of cells at D6. Activation of H3R had no effect on viability or apoptosis, whereas inhibition of H3R increased TNF alpha-induced apoptosis. Stimulation of C2C12 cells with TNF alpha increased Nlrp3 mRNA expression at D3 and D6. Moreover, TNF alpha reduced the expression of myogenesis markers MyoD1, Myogenin, and Myosin-2 at D3 and D6. H3R attenuated TNF alpha-induced expression of Nlrp3 and further inhibited the myogenesis marker expression; while H3R -blockage enhanced the proinflammatory effects of TNF alpha and increased the myogenesis marker expression. TNF alpha-induced secretion of mature IL-1 beta was dependent on the activation of the NLRP3 inflammasome, as shown by the reduced secretion of mature IL-1 beta upon treatment of the cells with the small molecule inhibitor of the NLRP3 inflammasome (MCC950). The activation of H3R reduced TNF alpha-induced IL-1 beta secretion, while the H3R blockage had an opposite effect. In conclusion, the modulation of H3R activity regulates the effects of TNF alpha on C2C12 myocyte differentiation and TNF alpha-induced activation of NLRP3 inflammasome. Thus, H3R signaling may represent a novel target for limiting postinjury muscle inflammation and muscle atrophy.
  • Penny, Amelia; Kroger, Bjorn (2019)
    The unprecedented diversifications in the fossil record of the early Palaeozoic (541-419 million years ago) increased both within-sample (alpha) and global (gamma) diversity, generating considerable ecological complexity. Faunal difference (beta diversity), including spatial heterogeneity, is thought to have played a major role in early Palaeozoic marine diversification, although alpha diversity is the major determinant of gamma diversity through the Phanerozoic. Drivers for this Phanerozoic shift from beta to alpha diversity are not yet resolved. Here, we evaluate the impacts of environmental and faunal heterogeneity on diversity patterns using a global spatial grid. We present early Palaeozoic genus-level alpha, beta and gamma diversity curves for molluscs, brachiopods, trilobites and echinoderms and compare them with measures of spatial lithological heterogeneity, which is our proxy for environmental heterogeneity. We find that alpha and beta diversity are associated with increased lithological heterogeneity, and that beta diversity declines over time while alpha increases. We suggest that the enhanced dispersal of marine taxa from the Middle Ordovician onwards facilitated increases in alpha diversity by encouraging the occupation of narrow niches and increasing the prevalence of transient species, simultaneously reducing spatial beta diversity. This may have contributed to a shift from beta to alpha diversity as the major determinant of gamma diversity increase over this critical evolutionary interval.
  • Laakasuo, Michael; Sundvall, Jukka; Drosinou, Maria-Anna (2017)
    The role of emotional disgust and disgust sensitivity in moral judgment and decision-making has been debated intensively for over 20 years. Until very recently, there were two main evolutionary narratives for this rather puzzling association. One of the models suggest that it was developed through some form of group selection mechanism, where the internal norms of the groups were acting as pathogen safety mechanisms. Another model suggested that these mechanisms were developed through hygiene norms, which were piggybacking on pathogen disgust mechanisms. In this study we present another alternative, namely that this mechanism might have evolved through sexual disgust sensitivity. We note that though the role of disgust in moral judgment has been questioned recently, few studies have taken disgust sensitivity to account. We present data from a large sample (N=1300) where we analyzed the associations between The Three Domain Disgust Scale and the most commonly used 12 moral dilemmas measuring utilitarian/deontological preferences with Structural Equation Modeling. Our results indicate that of the three domains of disgust, only sexual disgust is associated with more deontological moral preferences. We also found that pathogen disgust was associated with more utilitarian preferences. Implications of the findings are discussed.
  • Hammaren, Henrik M.; Virtanen, Anniina T.; Abraham, Bobin George; Peussa, Heidi; Hubbard, Stevan R.; Silvennoinen, Olli (2019)
    Background: Janus kinases (JAKs; JAK1 to JAK3 and tyrosine kinase 2) mediate cytokine signals in the regulation of hematopoiesis and immunity. JAK2 clinical mutations cause myeloproliferative neoplasms and leukemia, and the mutations strongly concentrate in the regulatory pseudokinase domain Janus kinase homology (JH) 2. Current clinical JAK inhibitors target the tyrosine kinase domain and lack mutation and pathway selectivity. Objective: We sought to characterize mechanisms and differences for pathogenic and cytokine-induced JAK2 activation to enable design of novel selective JAK inhibitors. Methods: We performed a systematic analysis of JAK2 activation requirements using structure-guided mutagenesis, cell-signaling assays, microscopy, and biochemical analysis. Results: Distinct structural requirements were identified for activation of different pathogenic mutations. Specifically, the predominant JAK2 mutation, V617F, is the most sensitive to structural perturbations in multiple JH2 elements (C helix [aC], Src homology 2-JH2 linker, and ATP binding site). In contrast, activation of K539L is resistant to most perturbations. Normal cytokine signaling shows distinct differences in activation requirements: JH2 ATP binding site mutations have only a minor effect on signaling, whereasJH2aCmutations reduce homomeric (JAK2-JAK2) erythropoietin signaling and almost completely abrogate heteromeric (JAK2-JAK1) IFN-gamma signaling, potentially by disrupting a dimerization interface on JH2. Conclusions: These results suggest that therapeutic approaches targeting the JH2 ATP binding site and aC could be effective in inhibiting most pathogenic mutations. JH2 ATP site targeting has the potential for reduced side effects by retaining erythropoietin and IFN-gamma functions. Simultaneously, however, we identified the JH2 aC interface as a potential target for pathway-selective JAK inhibitors in patients with diseases with unmutated JAK2, thus providing new insights into the development of novel pharmacologic interventions.
  • Cruz, Gabriela; Grent-'t-Jong, Tineke; Krishnadas, Rajeev; Palva, J. Matias; Palva, Satu; Uhlhaas, Peter J. (2021)
    Long-Range Temporal Correlations (LRTCs) index the capacity of the brain to optimally process information. Previous research has shown that patients with chronic schizophrenia present altered LRTCs at alpha and beta oscillations. However, it is currently unclear at which stage of schizophrenia aberrant LRTCs emerge. To address this question, we investigated LRTCs in resting-state magnetoencephalographic (MEG) recordings obtained from patients with affective disorders and substance abuse (clinically at low-risk of psychosis, CHR-N), patients at clinical high-risk of psychosis (CHR-P) (n = 115), as well as patients with a first episode (FEP) (n = 25). Matched healthy controls (n = 47) served as comparison group. LRTCs were obtained for frequencies from 4 to 40 Hz and correlated with clinical and neuropsychological data. In addition, we examined the relationship between LRTCs and transition to psychosis in CHR-P participants, and the relationship between LRTC and antipsychotic medication in FEP participants. Our results show that participants from the clinical groups have similar LRTCs to controls. In addition, LRTCs did not correlate with clinical and neurocognitive variables across participants nor did LRTCs predict transition to psychosis. Therefore, impaired LRTCs do not reflect a feature in the clinical trajectory of psychosis. Nevertheless, reduced LRTCs in the beta-band over posterior sensors of medicated FEP participants indicate that altered LRTCs may appear at the onset of the illness. Future studies are needed to elucidate the role of anti-psychotic medication in altered LRTCs.
  • Doccini, Stefano; Marchese, Maria; Morani, Federica; Gamaldi, Nicola; Mero, Serena; Pezzini, Francesco; Soliymani, Rabah; Santi, Melissa; Signore, Giovanni; Ogi, Asahi; Rocchiccioli, Silvia; Kanninen, Katja M.; Simonati, Alessandro; Lalowski, Maciej; Santorelli, Filippo Maria (2022)
    CLN5 disease (MIM: 256731) represents a rare late-infantile form of neuronal ceroid lipofuscinosis (NCL), caused by mutations in the CLN5 gene that encodes the CLN5 protein (CLN5p), whose physiological roles stay unanswered. No cure is currently available for CLN5 patients and the opportunities for therapies are lagging. The role of lysosomes in the neuro-pathophysiology of CLN5 disease represents an important topic since lysosomal proteins are directly involved in the primary mechanisms of neuronal injury occurring in various NCL forms. We developed and implemented a lysosome-focused, label-free quantitative proteomics approach, followed by functional validations in both CLN5-knockout neuronal-like cell lines and Cln5−/− mice, to unravel affected pathways and modifying factors involved in this disease scenario. Our results revealed a key role of CLN5p in lipid homeostasis and sphingolipid metabolism and highlighted mutual NCL biomarkers scored with high lysosomal confidence. A newly generated cln5 knockdown zebrafish model recapitulated most of the pathological features seen in NCL disease. To translate the findings from in-vitro and preclinical models to patients, we evaluated whether two FDA-approved drugs promoting autophagy via TFEB activation or inhibition of the glucosylceramide synthase could modulate in-vitro ROS and lipid overproduction, as well as alter the locomotor phenotype in zebrafish. In summary, our data advance the general understanding of disease mechanisms and modifying factors in CLN5 disease, which are recurring in other NCL forms, also stimulating new pharmacological treatments.
  • Govaere, Olivier; Petersen, Sine Kragh; Martinez-Lopez, Nuria; Wouters, Jasper; Van Haele, Matthias; Mancina, Rosellina M.; Jamialahmadi, Oveis; Bilkei-Gorzo, Orsolya; Lassen, Pierre Bel; Darlay, Rebecca; Peltier, Julien; Palmer, Jeremy M.; Younes, Ramy; Tiniakos, Dina; Aithal, Guruprasad P.; Allison, Michael; Vacca, Michele; Goransson, Melker; Berlinguer-Palmini, Rolando; Clark, James E.; Drinnan, Michael J.; Yki-Järvinen, Hannele; Dufour, Jean-Francois; Ekstedt, Mattias; Francque, Sven; Petta, Salvatore; Bugianesi, Elisabetta; Schattenberg, Jorn M.; Day, Christopher P.; Cordell, Heather J.; Topal, Baki; Clement, Karine; Romeo, Stefano; Ratziu, Vlad; Roskams, Tania; Daly, Ann K.; Anstee, Quentin M.; Trost, Matthias; Hartlova, Anetta (2022)
    Background & Aims: Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood. Methods: A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1(-/-) and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and ex vivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank. Results: MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a proinflammatory phenotype and the release of cytokines such as TNF-alpha Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients. Conclusions: Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is a chronic disease primarily caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary lifestyle. Herein, we show that the macrophage scavenger receptor MSR1, an innate immune receptor, mediates lipid uptake and accumulation in Kupffer cells, resulting in liver inflammation and thereby promoting the progression of NAFLD in humans and mice. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
  • Porkka-Heiskanen, Tarja; Wigren, Henna-Kaisa (2020)
    One of the key features of sleep is that if the duration of a waking period is prolonged, the following sleep period will be longer, including more slow-wave activity. This homeostasis is explained by production of sleep pressure that accumulates during the waking period. It is generally accepted that neuronal activity, in one way or other, is the driving force for accumulation of sleep pressure, both during spontaneous sleep-wake cycle and during prolonged wakefulness. Prolonged wakefulness is associated with increased energy consumption, production of danger signals and modulations in neural plasticity. Data derived from experiments with Drosophila melanogaster introduces a fascinating window to the basic mechanisms of sleep and sleep homeostasis, and undoubtedly sheds light to the mechanisms of sleep regulation also in humans. However, the existence of substantial cortex, which is regarded as a key actor in mammalian NREM sleep regulation, will add to the complexity of the regulatory circuits.
  • Nurmi, Katariina; Niemi, Katri; Kareinen, Ilona; Silventoinen, Kristiina; Lorey, Martina B; Chen, Yan; Kouri, Vesa‐Petteri; Parantainen, Jukka; Juutilainen, Timo; Öörni, Katariina; Kovanen, Petri T; Nordström, Dan; Matikainen, Sampsa; Eklund, Kari K (2021)
    Objectives The NLRP3 inflammasome plays a key role in arterial wall inflammation. In this study, we elucidated the role of serum lipoproteins in the regulation of NLRP3 inflammasome activation by serum amyloid A (SAA) and other inflammasome activators. Methods The effect of lipoproteins on the NLRP3 inflammasome activation was studied in primary human macrophages and THP-1 macrophages. The effect of oxidised low-density lipoprotein (LDL) was examined in an in vivo mouse model of SAA-induced peritoneal inflammation. Results Native and oxidised high-density lipoproteins (HDL3) and LDLs inhibited the interaction of SAA with TLR4. HDL3 and LDL inhibited the secretion of interleukin (IL)-1 beta and tumor necrosis factor by reducing their transcription. Oxidised forms of these lipoproteins reduced the secretion of mature IL-1 beta also by inhibiting the activation of NLRP3 inflammasome induced by SAA, ATP, nigericin and monosodium urate crystals. Specifically, oxidised LDL was found to inhibit the inflammasome complex formation. No cellular uptake of lipoproteins was required, nor intact lipoprotein particles for the inhibitory effect, as the lipid fraction of oxidised LDL was sufficient. The inhibition of NLRP3 inflammasome activation by oxidised LDL was partially dependent on autophagy. Finally, oxidised LDL inhibited the SAA-induced peritoneal inflammation and IL-1 beta secretion in vivo. Conclusions These findings reveal that both HDL3 and LDL inhibit the proinflammatory activity of SAA and this inhibition is further enhanced by lipoprotein oxidation. Thus, lipoproteins possess major anti-inflammatory functions that hinder the NLRP3 inflammasome-activating signals, particularly those exerted by SAA, which has important implications in the pathogenesis of cardiovascular diseases.
  • Poikonen, Hanna; Toiviainen, Petri; Tervaniemi, Mari (2018)
    Expertise in music has been investigated for decades and the results have been applied not only in composition, performance and music education, but also in understanding brain plasticity in a larger context. Several studies have revealed a strong connection between auditory and motor processes and listening to and performing music, and music imagination. Recently, as a logical next step in music and movement, the cognitive and affective neuro-sciences have been directed towards expertise in dance. To understand the versatile and overlapping processes during artistic stimuli, such as music and dance, it is necessary to study them with continuous naturalistic stimuli. Thus, we used long excerpts from the contemporary dance piece Carmen presented with and without music to professional dancers, musicians, and laymen in an EEG laboratory. We were interested in the cortical phase synchrony within each participant group over several frequency bands during uni- and multimodal processing. Dancers had strengthened theta and gamma synchrony during music relative to silence and silent dance, whereas the presence of music decreased systematically the alpha and beta synchrony in musicians. Laymen were the only group of participants with significant results related to dance. Future studies are required to understand whether these results are related to some other factor (such as familiarity to the stimuli), or if our results reveal a new point of view to dance observation and expertise.
  • Ade, P. A. R.; Keihänen, E.; Kurki-Suonio, H.; Suur-Uski, A. -S.; Valiviita, J.; Planck Collaboration (2015)
    Any variation in the fundamental physical constants, more particularly in the fine structure constant, a, or in the mass of the electron, me, affects the recombination history of the Universe and cause an imprint on the cosmic microwave background angular power spectra. We show that the Planck data allow one to improve the constraint on the time variation of the fine structure constant at redshift z - 10(3) by about a factor of 5 compared to WMAP data, as well as to break the degeneracy with the Hubble constant, H-0. In addition to a, we can set a constraint on the variation in the mass of the electron, me, and in the simultaneous variation of the two constants. We examine in detail the degeneracies between fundamental constants and the cosmological parameters, in order to compare the limits obtained from Planck and WMAP and to determine the constraining power gained by including other cosmological probes. We conclude that independent time variations of the fine structure constant and of the mass of the electron are constrained by Planck to Delta alpha/alpha = (3.6 +/- 3.7) x 10(-3) and Delta m(e)/m(e) = (4 +/- 11) x 10(-3) at the 68% confidence level. We also investigate the possibility of a spatial variation of the fine structure constant. The relative amplitude of a dipolar spatial variation in a (corresponding to a gradient across our Hubble volume) is constrained to be delta alpha/alpha = (-2.4 +/- 3.7) x 10(-2).
  • Reijnders, Margot R. F.; Janowski, Robert; Alvi, Mohsan; Self, Jay E.; van Essen, Ton J.; Vreeburg, Maaike; Rouhl, Rob P. W.; Stevens, Servi J. C.; Stegmann, Alexander P. A.; Schieving, Jolanda; Pfundt, Rolph; van Dijk, Katinke; Smeets, Eric; Stumpel, Connie T. R. M.; Bok, Levinus A.; Cobben, Jan Maarten; Engelen, Marc; Mansour, Sahar; Whiteford, Margo; Chandler, Kate E.; Douzgou, Sofia; Cooper, Nicola S.; Tan, Ene-Choo; Foo, Roger; Lai, Angeline H. M.; Rankin, Julia; Green, Andrew; Lönnqvist, Tuula; Isohanni, Pirjo; Williams, Shelley; Ruhoy, Ilene; Carvalho, Karen S.; Dowling, James J.; Lev, Dorit L.; Sterbova, Katalin; Lassuthova, Petra; Neupauerova, Jana; Waugh, Jeff L.; Keros, Sotirios; Clayton-Smith, Jill; Smithson, Sarah F.; Brunner, Han G.; van Hoeckel, Ceciel; Anderson, Mel; Clowes, Virginia E.; Siu, Victoria Mok; Selber, Paulo; Leventer, Richard J.; Nellaker, Christoffer; Niessing, Dierk; DDD Study (2018)
    Background De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. Objectives T o delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. Methods Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotypephenotype correlations by analysis of both recurrent mutations as well as mutation classes. Results We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. Conclusion We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.