Browsing by Subject "BLOOD"

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  • Aspelund, Aleksanteri; Antila, Salli; Proulx, Steven T.; Karlsen, Tine Veronica; Karaman, Sinem; Detmar, Michael; Wiig, Helge; Alitalo, Kari (2015)
    The central nervous system (CNS) is considered an organ devoid of lymphatic vasculature. Yet, part of the cerebrospinal fluid (CSF) drains into the cervical lymph nodes (LNs). The mechanism of CSF entry into the LNs has been unclear. Here we report the surprising finding of a lymphatic vessel network in the dura mater of the mouse brain. We show that dural lymphatic vessels absorb CSF from the adjacent subarachnoid space and brain interstitial fluid (ISF) via the glymphatic system. Dural lymphatic vessels transport fluid into deep cervical LNs (dcLNs) via foramina at the base of the skull. In a transgenic mouse model expressing a VEGF-C/D trap and displaying complete aplasia of the dural lymphatic vessels, macromolecule clearance from the brain was attenuated and transport from the subarachnoid space into dcLNs was abrogated. Surprisingly, brain ISF pressure and water content were unaffected. Overall, these findings indicate that the mechanism of CSF flow into the dcLNs is directly via an adjacent dural lymphatic network, which may be important for the clearance of macromolecules from the brain. Importantly, these results call for a reexamination of the role of the lymphatic system in CNS physiology and disease.
  • McGarvey, Alison C.; Rybtsov, Stanislav; Souilhol, Celine; Tamagno, Sara; Rice, Ritva; Hills, David; Godwin, Duncan; Rice, David; Tomlinson, Simon R.; Medvinsky, Alexander (2017)
    In the developing embryo, hematopoietic stem cells (HSCs) emerge from the aorta-gonad-mesonephros (AGM) region, but the molecular regulation of this process is poorly understood. Recently, the progression from E9.5 to E10.5 and polarity along the dorso-ventral axis have been identified as clear demarcations of the supportive HSC niche. To identify novel secreted regulators of HSC maturation, we performed RNA sequencing over these spatiotemporal transitions in the AGM region and supportive OP9 cell line. Screening several proteins through an ex vivo reaggregate culture system, we identify BMP ER as a novel positive regulator of HSC development. We demonstrate that BMP ER is associated with BMP signaling inhibition, but is transcriptionally induced by BMP4, suggesting that BMP ER contributes to the precise control of BMP activity within the AGM region, enabling the maturation of HSCs within a BMP-negative environment. These findings and the availability of our transcriptional data through an accessible interface should provide insight into the maintenance and potential derivation of HSCs in culture.
  • FINNPEC (2018)
    Preeclampsia (PE) is a complex pregnancy disorder. It is not extensively known how the metabolic alterations of PE women contribute to the metabolism of newborn. We applied liquid chromatography-mass spectrometry (LC-MS) based non-targeted meta bolomics to determine whether the metabolic profile of plasma from umbilical cord differs between infants born to PE and non-PE pregnancies in the FINNPEC study. Cord plasma was available from 42 newborns born from PE and 53 from non-PE pregnancies. 133 molecular features differed between PE and non-PE newborns after correction for multiple testing. Decreased levels of 4-pyridoxic acid were observed in the cord plasma samples of PE newborns when compared to non-PE newborns. Compounds representing following areas of metabolism were increased in the cord plasma of PE newborns: urea and creatine metabolism; carnitine biosynthesis and acylcarnitines; putrescine metabolites; tryptophan metabolism and phosphatidylcholines. To our knowledge, this study is the first one to apply LC-MS based meta bolomics in cord plasma of PE newborns. We demonstrate that this strategy provides a global picture of the widespread metabolic alterations associated with PE and particularly the elevated levels of carnitine precursors and trimethylated compounds appear to be associated with PE at birth.
  • Haegerling, Rene; Pollmann, Cathrin; Andreas, Martin; Schmidt, Christian; Nurmi, Harri; Adams, Ralf H.; Alitalo, Kari; Andresen, Volker; Schulte-Merker, Stefan; Kiefer, Friedemann (2013)
  • Cremers, Eline M. P.; de Witte, Theo; de Wreede, Liesbeth; Eikema, Diderik-Jan; Koster, Linda; van Biezen, Anja; Finke, Jurgen; Socie, Gerard; Beelen, Dietrich; Maertens, Johan; Nagler, Arnon; Kobbe, Guido; Ziagkos, Dimitris; Itälä-Remes, Maija; Gedde-Dahl, Tobias; Sierra, Jorge; Niederwieser, Dietger; Ljungman, Per; Beguin, Yves; Ozkurt, Zubeyde Nur; Anagnostopoulos, Achilles; Jindra, Pavel; Robin, Marie; Kröger, Nicolaus (2019)
    Most myelodysplastic syndromes (MDS)-patients receive multiple red blood cell transfusions (RBCT). Transfusions may cause iron-related toxicity and mortality, influencing outcome after allogeneic HSCT. This prospective non-interventional study evaluated 222 MDS and CMML patients undergoing HSCT. Overall survival (OS), relapse-free survival (RFS), non-relapse mortality (NRM), and relapse incidence (RI) at 36 months were 52%, 44%, 25%, and 31%, respectively. Age, percentage of marrow blasts and severe comorbidities impacted OS. RFS was significantly associated with RBCT burden prior to HSCT (HR: 1.7; p = .02). High ferritin levels had a significant negative impact on OS and RI, but no impact on NRM. Administration of iron chelation therapy prior to HSCT did not influence the outcome, but early iron reduction after HSCT (started before 6 months) improved RFS significantly after transplantation (56% in the control group vs. 90% in the treated group, respectively; p = .04). This study illustrates the impact of RBCT and related parameters on HSCT-outcome. Patients with an expected prolonged survival after transplantation may benefit from early iron reduction therapy after transplantation.
  • Silvennoinen, R.; Anttila, P.; Saily, M.; Lundan, T.; Heiskanen, J.; Siitonen, T. M.; Kakko, S.; Putkonen, M.; Ollikainen, H.; Terava, V.; Kutila, A.; Launonen, K.; Rasanen, A.; Sikio, A.; Suominen, M.; Bazia, P.; Kananen, K.; Selander, T.; Kuittinen, T.; Remes, K.; Jantunen, E. (2016)
    The most common means of mobilizing autologous stem cells is G-CSF alone or combined with cyclophosphamide (CY) to obtain sufficient CD34(+) cells for one to two transplants. There are few prospective, randomized studies investigating mobilization regimens in multiple myeloma (MM), especially after lenalidomide-based induction. We designed this prospective, randomized study to compare low-dose CY 2 g/m(2)+G-CSF (arm A) and G-CSF alone (arm B) after lenalidomide-based up-front induction in MM. Of the 80 initially randomized patients, 69 patients were evaluable, 34 and 35 patients in arms A and B, respectively. The primary end point was the proportion of patients achieving a yield of >= 3x10(6)/kg CD34(+) cells with 1 - 2 aphereses, which was achieved in 94% and 77% in arms A and B, respectively (P = 0.084). The median number of aphereses needed to reach the yield of >= 3x10(6)/kg was lower in arm A than in arm B (1 vs 2, P = 0.035). Two patients needed plerixafor in arm A and five patients in arm B (P = 0.428). Although CY-based mobilization was more effective, G-CSF alone was successful in a great majority of patients to reach the defined collection target after three cycles of lenalidomide-based induction.
  • Kelkka, Tiina; Savola, Paula; Bhattacharya, Dipabarna; Huuhtanen, Jani; Lönnberg, Tapio; Kankainen, Matti; Paalanen, Kirsi; Tyster, Mikko; Lepistö, Maija; Ellonen, Pekka; Smolander, Johannes; Eldfors, Samuli; Yadav, Bhagwan; Khan, Sofia; Koivuniemi, Riitta; Sjöwall, Christopher; Elo, Laura L.; Lahdesmaki, Harri; Maeda, Yuka; Nishikawa, Hiroyashi; Leirisalo-Repo, Marjatta; Sokka-Isler, Tuulikki; Mustjoki, Satu (2020)
    Rheumatoid arthritis (RA) is a complex autoimmune disease targeting synovial joints. Traditionally, RA is divided into seropositive (SP) and seronegative (SN) disease forms, the latter consisting of an array of unrelated diseases with joint involvement. Recently, we described a severe form of SN-RA that associates with characteristic joint destruction. Here, we sought biological characteristics to differentiate this rare but aggressive anti-citrullinated peptide antibody-negative destructive RA (CND-RA) from early seropositive (SP-RA) and seronegative rheumatoid arthritis (SN-RA). We also aimed to study cytotoxic CD8+ lymphocytes in autoimmune arthritis. CND-RA, SP-RA and SN-RA were compared to healthy controls to reveal differences in T-cell receptor beta (TCR beta) repertoire, cytokine levels and autoantibody repertoires. Whole-exome sequencing (WES) followed by single-cell RNA-sequencing (sc-RNA-seq) was performed to study somatic mutations in a clonally expanded CD8+ lymphocyte population in an index patient. A unique TCR beta signature was detected in CND-RA patients. In addition, CND-RA patients expressed higher levels of the bone destruction-associated TNFSF14 cytokine. Blood IgG repertoire from CND-RA patients recognized fewer endogenous proteins than SP-RA patients' repertoires. Using WES, we detected a stable mutation profile in the clonally expanded CD8+ T-cell population characterized by cytotoxic gene expression signature discovered by sc-RNA-sequencing. Our results identify CND-RA as an independent RA subset and reveal a CND-RA specific TCR signature in the CD8+ lymphocytes. Improved classification of seronegative RA patients underlines the heterogeneity of RA and also, facilitates development of improved therapeutic options for the treatment resistant patients.
  • Garderet, Laurent; Ziagkos, Dimitris; Van Biezen, Anja; Iacobelli, Simona; Finke, Juergen; Maertens, Johan; Volin, Liisa; Ljungman, Per; Chevallier, Patrice; Passweg, Jakob; Schaap, Nicolaas; Beelen, Dietrich; Nagler, Arnon; Blaise, Didier; Poire, Xavier; Yakoub-Agha, Ibrahim; Lenhoff, Stig; Craddock, Charles; Schots, Rik; Rambaldi, Alessandro; Sanz, Jaime; Jindra, Pavel; Mufti, Ghulam J.; Robin, Marie; Kroeger, Nicolaus (2018)
    The deletion (5q) karyotype (del [5q]) in patients with myelodysplastic syndrome (MDS) is the most common karyotypic abnormality in de novo MDS. An increased number of blasts and additional karyotypic abnormalities (del [al]+) are associated with a poor outcome. We analyzed the outcome of allogeneic hematopoietic cell transplants (HCT) in patients suffering from MDS with only del (5q) or del (5q)+. A total of 162 patients, of median age 54 years (range, 9 to 73), having MDS and del (5q) abnormalities received HCT from identical siblings (n = 87) or unrelated donors (n = 75). The cumulative incidence of nonrelapse mortality and relapse incidence at 4 years was 29% (95% CI, 22 to 36) and 46% (95% CI, 38 to 54), whereas the estimated 4 year survival, relapse-free and overall, was 25% (95% CI, 18 to 33) and 30% (95% CI, 23 to 38), respectively. In a multivariate analysis patients with del (5q) and a blast excess displayed poorer survival (hazard ratio, 2.38; 95% CI, 1.44 to 3.93; P
  • Nuotio, Marja-Liisa; Pervjakova, Natalia; Joensuu, Anni; Karhunen, Ville; Hiekkalinna, Tero; Milani, Lili; Kettunen, Johannes; Järvelin, Marjo-Riitta; Jousilahti, Pekka; Metspalu, Andres; Salomaa, Veikko; Kristiansson, Kati; Perola, Markus (2020)
    The role of metabolic syndrome (MetS) as a preceding metabolic state for type 2 diabetes and cardiovascular disease is widely recognised. To accumulate knowledge of the pathological mechanisms behind the condition at the methylation level, we conducted an epigenome-wide association study (EWAS) of MetS and its components, testing 1187 individuals of European ancestry for approximately 470 000 methylation sites throughout the genome. Methylation site cg19693031 in gene TXNIP -previously associated with type 2 diabetes, glucose and lipid metabolism, associated with fasting glucose level (P=1.80x10(-8)). Cg06500161 in gene ABCG1 associated both with serum triglycerides (P=5.36x10(-9)) and waist circumference (P=5.21x10(-9)). The previously identified type 2 diabetes-associated locus cg08309687 in chromosome 21 associated with waist circumference for the first time (P=2.24x10(-7)). Furthermore, a novel HDL association with cg17901584 in chromosome 1 was identified (P=7.81x10(-8)). Our study supports previous genetic studies of MetS, finding that lipid metabolism plays a key role in pathology of the syndrome. We provide evidence regarding a close interplay with glucose metabolism. Finally, we suggest that in attempts to identify methylation loci linking separate MetS components, cg19693031 appears to represent a strong candidate.
  • Hannon, Eilis; Dempster, Emma; Viana, Joana; Burrage, Joe; Smith, Adam R.; Macdonald, Ruby; St Clair, David; Mustard, Colette; Breen, Gerome; Therman, Sebastian; Kaprio, Jaakko; Toulopoulou, Timothea; Pol, Hilleke E. Hulshoff; Bohlken, Marc M.; Kahn, Rene S.; Nenadic, Igor; Hultman, Christina M.; Murray, Robin M.; Collier, David A.; Bass, Nick; Gurling, Hugh; McQuillin, Andrew; Schalkwyk, Leonard; Mill, Jonathan (2016)
    Background: Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. Results: We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease. Conclusions: This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.
  • Netherlands, Edward C.; Cook, Courtney A.; Du Preez, Louis H.; Vanhove, Maarten P.M.; Brendonck, Luc; Smit, Nico J. (2020)
    Haemogregarine (Apicomplexa: Adeleorina) blood parasites are commonly reported from anuran hosts. Dactylosomatidae (Jakowska and Nigrelli, 1955) is a group of haemogregarines comprising Dactylosoma Labbe, 1894 and Babesiosoma Jakowska and Nigrelli, 1956. Currently Dactylosoma and Babesiosoma contain five recognised species each. In the current study, a total of 643 anurans, comprising 38 species, 20 genera, and 13 families were collected from South Africa (n = 618) and Belgium (n = 25), and their blood screened for the presence of dactylosomatid parasites. Three anuran species were found infected namely, Ptychadena anchietae (Bocage, 1868) and Sclerophrys gutturalis (Power, 1927) from South Africa, and Pelophylax lessonae (Camerano, 1882) from Belgium. Based on morphological characteristics, morphometrics and molecular results a new dactylosomatid, Dactylosoma kermiti n. sp. is described form Pty. anchietae and Scl. gutturalis. The species of Dactylosoma isolated from Pel. lessonae could not, based on morphological or molecular analysis, be identified to species level. Phylogenetic analysis shows species of Dactylosoma infecting anurans as a monophyletic group separate from the other haemogregarine groups. Additionally, the mosquitoes Uranotaenia (Pseudoficalbia) mashonaensis Theobald, 1901 and U. (Pfc.) montana Ingram and De Meillon, 1927 were observed feeding on Scl. gutturalis in situ and possible dividing stages of this new parasite were observed in the mosquitoes. This study is the first to describe a dactylosomatid parasite based on morphological and molecular data from Africa as well as observe potential stages in possible dipteran vectors.
  • Iljukov, Sergei; Kauppi, Jukka-Pekka; Uusitalo, Arja L. T.; Peltonen, Juha E.; Schumacher, Yorck O. (2020)
    The purpose of this research was to evaluate the performances of female middle- and long-distance runners before and after the implementation of a new antidoping strategy (the Athlete Biological Passport [ABP]) in a country accused of systematic doping. A retrospective analysis of the results of Russian National Championships from 2008 to 2017 was performed. The 8 best female performances for the 800-m, 1500-m, 3000-m steeplechase, 5000-m, and 10,000-m events from the semifinals and finals were analyzed. The yearly number of athletes fulfilling standard qualifications for international competitions was also evaluated. Overall, numbers of athletes banned for doping in 2008-2017 were calculated. As a result, 4 events (800, 1500, 5000 [all P
  • van Gelder, Michel; Ziagkos, Dimitris; de Wreede, Liesbeth; van Biezen, Anja; Dreger, Peter; Gramatzki, Martin; Stelljes, Matthias; Andersen, Niels Smedegaard; Schaap, Nicolaas; Vitek, Antonin; Beelen, Dietrich; Lindstrom, Vesa; Finke, Juergen; Passweg, Jacob; Eder, Matthias; Machaczka, Maciej; Delgado, Julio; Krueger, William; Raida, Ludek; Socie, Gerard; Jindra, Pavel; Afanasyev, Boris; Wagner, Eva; Chalandon, Yves; Henseler, Anja; Schoenland, Stefan; Kroeger, Nicolaus; Schetelig, Johannes; CLL Subcomm Chronic Malignancies W; European Soc Blood Marrow Transpla (2017)
    Patients with chronic lymphocytic leukemia with del(17p) or del(11q) have poor long-term prognosis with targeted therapies. Conversely, this retrospective European Society for Blood and Marrow Transplantation registry study shows that young high cytogenetic risk responsive patients with human leukocyte antigen-matched donors have a high 8-year progression-free survival and low 2-year non-relapse mortality after allogeneic stem cell transplantation. This treatment then may compare favorably with targeted therapies for younger high cytogenetic risk patients. Background: Patients with genetically high-risk relapsed/refractory chronic lymphocytic leukemia have shorter median progression-free survival (PFS) with kinase-and BCL2-inhibitors (KI, BCL2i). Allogeneic hematopoietic stem cell transplantation (alloHCT) may result in sustained PFS, especially in younger patients because of its age-dependent non-relapse mortality (NRM) risk, but outcome data are lacking for this population. Patients and Methods: Risk factors for 2-year NRM and 8-year PFS were identified in patients <50 years in an updated European Society for Blood and Marrow Transplantation registry cohort (n = 197; median follow-up, 90.4 months) by Cox regression modeling, and predicted probabilities of NRM and PFS of 2 reference patients with favorable or unfavorable characteristics were plotted. Results: Predictors for poor 8-year PFS were no remission at the time of alloHCT (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.1-2.5) and partially human leukocyte antigen (HLA)-mismatched unrelated donor (HR, 2.8; 95% CI, 1.5-5.2). The latter variable also predicted a higher risk of 2-year NRM (HR, 4.0; 95% CI, 1.4-11.6) compared with HLA-matched sibling donors. Predicted 2-year NRM and 8-year PFS of a high cytogenetic risk (del(17p) and/or del(11q)) patient in remission with a matched related donor were 12% (95% CI, 3%-22%) and 54% (95% CI, 38%-69%), and for an unresponsive patient with a female partially HLA-matched unrelated donor 37% (95% CI, 12%-62%) and 38% (95% CI, 13%-63%). Conclusion: Low predicted NRM and high 8-year PFS in favorable transplant high cytogenetic risk patients compares favorably with outcomes with KI or BCL2i. Taking into account the amount of uncertainty for predicting survival after alloHCT and after sequential administration of KI and BCL2i, alloHCT remains a valid option for younger patients with high cytogenetic risk chronic lymphocytic leukemia with a well-HLA-matched donor. (C) 2017 Elsevier Inc. All rights reserved.
  • Mantysaari, P.; Mantysaari, E. A.; Kokkonen, T.; Mehtio, T.; Kajava, S.; Grelet, C.; Lidauer, P.; Lidauer, M. H. (2019)
    The inclusion of feed intake and efficiency traits in dairy cow breeding goals can lead to increased risk of metabolic stress. An easy and inexpensive way to monitor postpartum energy status (ES) of cows is therefore needed. Cows' ES can be estimated by calculating the energy balance from energy intake and output and predicted by indicator traits such as change in body weight (Delta BW), change in body condition score (Delta BCS), milk fat:protein ratio (FPR), or milk fatty acid (FA) composition. In this study, we used blood plasma nonesterified fatty acids (NEFA) concentration as a biomarker for ES. We determined associations between NEFA concentration and ES indicators and evaluated the usefulness of body and milk traits alone, or together, in predicting ES of the cow. Data were collected from 2 research herds during 2013 to 2016 and included 137 Nordic Red dairy cows, all of which had a first lactation and 59 of which also had a second lactation. The data included daily body weight, milk yield, and feed intake and monthly BCS. Plasma samples for NEFA were collected twice in lactation wk 2 and 3 and once in wk 20. Milk samples for analysis of fat, protein, lactose, and FA concentrations were taken on the blood sampling days. Plasma NEFA concentration was higher in lactation wk 2 and 3 than in wk 20 (0.56 +/- 0.30, 0.43 +/- 0.22, and 0.13 +/- 0.06 mmol/L, respectively; all means +/- standard deviation). Among individual indicators, C18:1 cis-9 and the sum of C18:1 in milk had the highest correlations (r = 0.73) with NEFA. Seven multiple linear regression models for NEFA prediction were developed using stepwise selection. Of the models that included milk traits (other than milk FA) as well as body traits, the best fit was achieved by a model with milk yield, FPR, Delta BW, Delta BCS, FPR x Delta BW, and days in milk. The model resulted in a cross-validation coefficient of determination (R(2)cv) of 0.51 and a root mean squared error (RMSE) of 0.196 mmol/L. When only milk FA concentrations were considered in the model, NEFA prediction was more accurate using measurements from evening milk than from morning milk (R(2)cv = 0.61 vs. 0.53). The best model with milk traits contained FPR, C10:0, C14:0, C18:1 cis-9, C18:1 cis-9 x C14:0, and days in milk (R(2)cv = 0.62; RMSE = 0.177 mmol/L). The most advanced model using both milk and body traits gave a slightly better fit than the model with only milk traits (R(2)cv = 0.63; RMSE = 0.176 mmol/L). Our findings indicate that ES of cows in early lactation can be monitored with moderately high accuracy by routine milk measurements.
  • Soininen, Leena; Mussalo-Rauhamaa, Helena (2021)
    This article summarizes the results of studies on the exposure of the Finnish Sami people to radioactive fallout and the estimations of the related cancer risk. We also discuss the lifestyle, genetic origin and diet of this population. The Sami people are an indigenous people who live in the northern part of Scandinavia and Finland. The review is based on the available scientific literature of Finnish Sami. The traditional Sami diet, high in animal products, persists in Sami groups still involved in reindeer-herding, but others have adopted the typical diet of western cultures. Studies have consistently shown an overall reduced cancer risk among the Finnish Sami people, except for stomach cancer among the Skolt Sami. Common cancers among the Finnish main population, such as prostate, breast and skin cancer are especially rare among the Finnish Sami. The incidence of cancer among the Finnish Sami are mostly similar to those of the Swedish and Norwegian Sami. To conclude, we observed no effect of radioactive pollution on cancer incidence. The lifestyles and environments of the Sami are changing, and their cancer mortality rate today is similar to that of the majority of the Finnish and western population.
  • Westra, Harm-Jan; Arends, Danny; Esko, Tonu; Peters, Marjolein J.; Schurmann, Claudia; Schramm, Katharina; Kettunen, Johannes; Yaghootkar, Hanieh; Fairfax, Benjamin P.; Andiappan, Anand Kumar; Li, Yang; Fu, Jingyuan; Karjalainen, Juha; Platteel, Mathieu; Visschedijk, Marijn; Weersma, Rinse K.; Kasela, Silva; Milani, Lili; Tserel, Liina; Peterson, Part; Reinmaa, Eva; Hofman, Albert; Uitterlinden, Andre G.; Rivadeneira, Fernando; Homuth, Georg; Petersmann, Astrid; Lorbeer, Roberto; Prokisch, Holger; Meitinger, Thomas; Herder, Christian; Roden, Michael; Grallert, Harald; Ripatti, Samuli; Perola, Markus; Wood, Andrew R.; Melzer, David; Ferrucci, Luigi; Singleton, Andrew B.; Hernandez, Dena G.; Knight, Julian C.; Melchiotti, Rossella; Lee, Bernett; Poidinger, Michael; Zolezzi, Francesca; Larbi, Anis; Wang, De Yun; van den Berg, Leonard H.; Veldink, Jan H.; Rotzschke, Olaf; Makino, Seiko; Salomaa, Veikko; Strauch, Konstantin; Voelker, Uwe; van Meurs, Joyce B. J.; Metspalu, Andres; Wijmenga, Cisca; Jansen, Ritsert C.; Franke, Lude (2015)
    The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn's disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus.
  • Petersen, Anders Ø.; Julienne, Hanna; Hyötyläinen, Tuulia; Sen, Partho; Fan, Yong; Pedersen, Helle Krogh; Jäntti, Sirkku; Hansen, Tue H.; Nielsen, Trine; Jørgensen, Torben; Hansen, Torben; Myers, Pernille Neve; Nielsen, H. Bjørn; Ehrlich, S. Dusko; Orešič, Matej; Pedersen, Oluf (2021)
    Knowledge about in vivo effects of human circulating C-6 hydroxylated bile acids (BAs), also called muricholic acids, is sparse. It is unsettled if the gut microbiome might contribute to their biosynthesis. Here, we measured a range of serum BAs and related them to markers of human metabolic health and the gut microbiome. We examined 283 non-obese and obese Danish adults from the MetaHit study. Fasting concentrations of serum BAs were quantified using ultra-performance liquid chromatography-tandem mass-spectrometry. The gut microbiome was characterized with shotgun metagenomic sequencing and genome-scale metabolic modeling. We find that tauro- and glycohyocholic acid correlated inversely with body mass index (P = 4.1e-03, P = 1.9e-05, respectively), waist circumference (P = 0.017, P = 1.1e-04, respectively), body fat percentage (P = 2.5e-03, P = 2.3e-06, respectively), insulin resistance (P = 0.051, P = 4.6e-4, respectively), fasting concentrations of triglycerides (P = 0.06, P = 9.2e-4, respectively) and leptin (P = 0.067, P = 9.2e-4). Tauro- and glycohyocholic acids, and tauro-a-muricholic acid were directly linked with a distinct gut microbial community primarily composed of Clostridia species (P = 0.037, P = 0.013, P = 0.027, respectively). We conclude that serum conjugated C-6-hydroxylated BAs associate with measures of human metabolic health and gut communities of Clostridia species. The findings merit preclinical interventions and human feasibility studies to explore the therapeutic potential of these BAs in obesity and type 2 diabetes.
  • Vijayan, Madhavi; Lee, Cheuk-Lun; Wong, Vera H. H.; Wang, Xia; Bai, Kungfeng; Wu, Jian; Koistinen, Hannu; Seppälä, Markku; Lee, Kai-Fai; Yeung, William S. B.; Ng, Ernest H. Y.; Chiu, Philip C. N. (2020)
    Decidual macrophages constitute 20-30% of the total leukocytes in the uterus of pregnant women, regulating the maternal immune tolerance and placenta development. Abnormal number or activities of decidual macrophages (dMs) are associated with fetal loss and pregnancy complications, such as preeclampsia. Monocytes differentiate into dMs in a decidua-specific microenvironment. Despite their important roles in pregnancy, the exact factors that regulate the differentiation into dMs remain unclear. Glycodelin-A (PAEP, hereafter referred to as GdA) is a glycoprotein that is abundantly present in the decidua, and plays an important role in fetomaternal defense and placental development. It modulates the differentiation and activity of several immune cell types residing in the decidua. In this study, we demonstrated that GdA induces the differentiation of human monocytes into dM-like phenotypes in terms of transcriptome, cell surface marker expression, secretome, and regulation of trophoblast and endothelial cell functions. We found that Sialic acid-binding Ig-like lectin 7 (Siglec-7) mediates the binding and biological actions of GdA in a sialic acid-dependent manner. We, therefore, suggest that GdA, induces the polarization of monocytes into dMs to regulate fetomatemal tolerance and placental development.
  • Nieminen, Janne K.; Niemi, Mirja; Sipponen, Taina; Salo, Harri M.; Klemetti, Paula; Färkkilä, Martti Antero; Vakkila, Jukka; Vaarala, Outi (2013)
  • Patel, Tirth K.; Habimana-Griffin, LeMoyne; Gao, Xuefeng; Xu, Baogang; Achilefu, Samuel; Alitalo, Kari; McKee, Celia A.; Sheehan, Patrick W.; Musiek, Erik S.; Xiong, Chengjie; Coble, Dean; Holtzman, David M. (2019)
    BackgroundAlzheimer's disease is characterized by two main neuropathological hallmarks: extracellular plaques of amyloid- (A) protein and intracellular aggregates of tau protein. Although tau is normally a soluble monomer that bind microtubules, in disease it forms insoluble, hyperphosphorylated aggregates in the cell body. Aside from its role in AD, tau is also involved in several other neurodegenerative disorders collectively called tauopathies, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), some forms of frontotemporal dementia, and argyrophilic grain disease (AGD). The prion hypothesis suggests that after an initial trigger event, misfolded forms of tau are released into the extracellular space, where they spread through different brain regions, enter cells, and seeding previously normal forms. Thus understanding mechanisms regulating the clearance of extracellular tau from the CNS is important. The discovery of a true lymphatic system in the dura and its potential role in mediating A pathology prompted us to investigate its role in regulating extracellular tau clearance.MethodsTo study clearance of extracellular tau from the brain, we conjugated monomeric human tau with a near-infrared dye cypate, and injected this labeled tau in the parenchyma of both wild-type and K14-VEGFR3-Ig transgenic mice, which lack a functional CNS lymphatic system. Following injection we performed longitudinal imaging using fluorescence molecular tomography (FMT) and quantified fluorescence to calculate clearance of tau from the brain. To complement this, we also measured tau clearance to the periphery by measuring plasma tau in both groups of mice.ResultsOur results show that a significantly higher amount of tau is retained in the brains of K14-VEGFR3-Ig vs. wild type mice at 48 and 72h post-injection and its subsequent clearance to the periphery is delayed. We found that clearance of reference tracer human serum albumin (HSA) was also significantly delayed in the K14-VEGFR3-Ig mice.ConclusionsThe dural lymphatic system appears to play an important role in clearance of extracellular tau, since tau clearance is impaired in the absence of functional lymphatics. Based on our baseline characterization of extracellular tau clearance, future studies are warranted to look at the interaction between tau pathology and efficiency of lymphatic function.