Browsing by Subject "VISUALIZATION"

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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.
  • Colombo, Jessica; Antkowiak, Adrien; Kogan, Konstantin; Kotila, Tommi; Elliott, Jenna; Guillotin, Audrey; Lappalainen, Pekka; Michelot, Alphée (2021)
    Actin polymerization provides force for vital processes of the eukaryotic cell, but our understanding of actin dynamics and energetics remains limited due to the lack of high-quality probes. Most current probes affect dynamics of actin or its interactions with actin-binding proteins (ABPs), and cannot track the bound nucleotide. Here, we identify a family of highly sensitive fluorescent nucleotide analogues structurally compatible with actin. We demonstrate that these fluorescent nucleotides bind to actin, maintain functional interactions with a number of essential ABPs, are hydrolyzed within actin filaments, and provide energy to power actin-based processes. These probes also enable monitoring actin assembly and nucleotide exchange with single-molecule microscopy and fluorescence anisotropy kinetics, therefore providing robust and highly versatile tools to study actin dynamics and functions of ABPs.
  • Haase, Robert; Fazeli, Elnaz; Legland, David; Doube, Michael; Culley, Sian; Belevich, Ilya; Jokitalo, Eija; Schorb, Martin; Klemm, Anna; Tischer, Christian (2022)
    Modern research in the life sciences is unthinkable without computational methods for extracting, quantifying and visualising information derived from microscopy imaging data of biological samples. In the past decade, we observed a dramatic increase in available software packages for these purposes. As it is increasingly difficult to keep track of the number of available image analysis platforms, tool collections, components and emerging technologies, we provide a conservative overview of software that we use in daily routine and give insights into emerging new tools. We give guidance on which aspects to consider when choosing the platform that best suits the user's needs, including aspects such as image data type, skills of the team, infrastructure and community at the institute and availability of time and budget.
  • Majander, Kerttu; Pfrengle, Saskia; Kocher, Arthur; Neukamm, Judith; du Plessis, Louis; Pla-Diaz, Marta; Arora, Natasha; Akgul, Gulfirde; Salo, Kati; Schats, Rachel; Inskip, Sarah; Oinonen, Markku; Valk, Heiki; Malve, Martin; Kriiska, Aivar; Onkamo, Paivi; Gonzalez-Candelas, Fernando; Kuehnert, Denise; Krause, Johannes; Schuenemann, Verena J. (2020)
    Syphilis is a globally re-emerging disease, which has marked European history with a devastating epidemic at the end of the 15th century. Together with non-venereal treponemal diseases, like bejel and yaws, which are found today in subtropical and tropical regions, it currently poses a substantial health threat worldwide. The origins and spread of treponemal diseases remain unresolved, including syphilis' potential introduction into Europe from the Americas. Here, we present the first genetic data from archaeological human remains reflecting a high diversity of Treponema pallidumin early modern Europe. Our study demonstrates that a variety of strains related to both venereal syphilis and yaws-causing T. pallidum subspecies were already present in Northern Europe in the early modern period. We also discovered a previously unknown T. pallidum lineage recovered as a sister group to yaws- and bejel-causing lineages. These findings imply a more complex pattern of geographical distribution and etiology of early treponemal epidemics than previously understood.
  • Patwardhan, Ardan; Brandt, Robert; Butcher, Sarah J.; Collinson, Lucy; Gault, David; Grunewald, Kay; Hecksel, Corey; Huiskonen, Juha T.; Iudin, Andrii; Jones, Martin L.; Korir, Paul K.; Koster, Abraham J.; Lagerstedt, Ingvar; Lawson, Catherine L.; Mastronarde, David; McCormick, Matthew; Parkinson, Helen; Rosenthal, Peter B.; Saalfeld, Stephan; Saibil, Helen R.; Sarntivijai, Sirarat; Valero, Irene Solanes; Subramaniam, Sriram; Swedlow, Jason R.; Tudose, Ilinca; Winn, Martyn; Kleywegt, Gerard J. (2017)
    The integration of cellular and molecular structural data is key to understanding the function of macromolecular assemblies and complexes in their in vivo context. Here we report on the outcomes of a workshop that discussed how to integrate structural data from a range of public archives. The workshop identified two main priorities: the development of tools and file formats to support segmentation (that is, the decomposition of a three-dimensional volume into regions that can be associated with defined objects), and the development of tools to support the annotation of biological structures.
  • Leskinen, Katarzyna; Tuomala, Henni; Wicklund, Anu; Horsma-Heikkinen, Jenni; Kuusela, Pentti; Skurnik, Mikael; Kiljunen, Saija (2017)
    Staphylococcus aureus is a commensal and pathogenic bacterium that causes infections in humans and animals. It is a major cause of nosocomial infections worldwide. Due to increasing prevalence of multidrug resistance, alternative methods to eradicate the pathogen are necessary. In this respect, polyvalent staphylococcal myoviruses have been demonstrated to be excellent candidates for phage therapy. Here we present the characterization of the bacteriophage vB_SauM-fRuSau02 (fRuSau02) that was isolated from a commercial Staphylococcus bacteriophage cocktail produced by Microgen (Moscow, Russia). The genomic analysis revealed that fRuSau02 is very closely related to the phage MSA6, and possesses a large genome (148,464 bp), with typical modular organization and a low G+ C (30.22%) content. It can therefore be classified as a new virus among the genus Twortlikevirus. The genome contains 236 predicted genes, 4 of which were interrupted by insertion sequences. Altogether, 78 different structural and virion-associated proteins were identified from purified phage particles by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The host range of fRuSau02 was tested with 135 strains, including 51 and 54 Staphylococcus aureus isolates from humans and pigs, respectively, and 30 coagulase-negative Staphylococcus strains of human origin. All clinical S. aureus strains were at least moderately sensitive to the phage, while only 39% of the pig strains were infected. Also, some strains of Staphylococcus intermedius, Staphylococcus lugdunensis, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus saprophyticus and Staphylococcus pseudointer were sensitive. We conclude that fRuSau02, a phage therapy agent in Russia, can serve as an alternative to antibiotic therapy against S. aureus.
  • He, Chen; Micallef, Luana; He, Liye; Peddinti, Gopal; Aittokallio, Tero; Jacucci, Giulio (2021)
    Understanding the quality of insight has become increasingly important with the trend of allowing users to post comments during visual exploration, yet approaches for qualifying insight are rare. This article presents a case study to investigate the possibility of characterizing the quality of insight via the interactions performed. To do this, we devised the interaction of a visualization tool—MediSyn—for insight generation. MediSyn supports five types of interactions: selecting, connecting, elaborating, exploring, and sharing. We evaluated MediSyn with 14 participants by allowing them to freely explore the data and generate insights. We then extracted seven interaction patterns from their interaction logs and correlated the patterns to four aspects of insight quality. The results show the possibility of qualifying insights via interactions. Among other findings, exploration actions can lead to unexpected insights; the drill-down pattern tends to increase the domain values of insights. A qualitative analysis shows that using domain knowledge to guide exploration can positively affect the domain value of derived insights. We discuss the study’s implications, lessons learned, and future research opportunities.
  • Skarp, C. P. A.; Akinrinade, O.; Nilsson, A. J. E.; Ellstrom, P.; Myllykangas, S.; Rautelin, H. (2015)
    Campylobacter jejuni is a major pathogen in bacterial gastroenteritis worldwide and can cause bacteremia in severe cases. C. jejuni is highly structured into clonal lineages of which the ST677CC lineage has been overrepresented among C. jejuni isolates derived from blood. In this study, we characterized the genomes of 31 C. jejuni blood isolates and 24 faecal isolates belonging to ST677CC in order to study the genome biology related to C. jejuni invasiveness. We combined the genome analyses with phenotypical evidence on serum resistance which was associated with phase variation of wcbK; a GDP-mannose 4,6-dehydratase involved in capsular biosynthesis. We also describe the finding of a Type III restriction-modification system unique to the ST-794 sublineage. However, features previously considered to be related to pathogenesis of C. jejuni were either absent or disrupted among our strains. Our results refine the role of capsule features associated with invasive disease and accentuate the possibility of methylation and restriction enzymes in the potential of C. jejuni to establish invasive infections. Our findings underline the importance of studying clinically relevant well-characterized bacterial strains in order to understand pathogenesis mechanisms important in human infections.
  • Hajkarim, Morteza Chalabi; Karjalainen, Ella; Osipovitch, Mikhail; Dimopoulos, Konstantinos; Gordon, Sandra L.; Ambri, Francesca; Rasmussen, Kasper Dindler; Gronbaek, Kirsten; Helin, Kristian; Wennerberg, Krister; Won, Kyoung-Jae (2022)
    Large-scale multiparameter screening has become increasingly feasible and straightforward to perform thanks to developments in technologies such as high-content microscopy and high-throughput flow cytometry. The automated toolkits for analyzing similarities and differences between large numbers of tested conditions have not kept pace with these technological developments. Thus, effective analysis of multiparameter screening datasets becomes a bottleneck and a limiting factor in unbiased interpretation of results. Here we introduce compaRe, a toolkit for large-scale multiparameter data analysis, which integrates quality control, data bias correction, and data visualization methods with a mass-aware gridding algorithm-based similarity analysis providing a much faster and more robust analyses than existing methods. Using mass and flow cytometry data from acute myeloid leukemia and myelodysplastic syndrome patients, we show that compaRe can reveal interpatient heterogeneity and recognizable phenotypic profiles. By applying compaRe to high-throughput flow cytometry drug response data in AML models, we robustly identified multiple types of both deep and subtle phenotypic response patterns, highlighting how this analysis could be used for therapeutic discoveries. In conclusion, compaRe is a toolkit that uniquely allows for automated, rapid, and precise comparisons of large-scale multiparameter datasets, including high-throughput screens.
  • Noguchi, Shuhei; Arakawa, Takahiro; Fukuda, Shiro; Furuno, Masaaki; Hasegawa, Akira; Hori, Fumi; Ishikawa-Kato, Sachi; Kaida, Kaoru; Kaiho, Ai; Kanamori-Katayama, Mutsumi; Kawashima, Tsugumi; Kojima, Miki; Kubosaki, Atsutaka; Manabe, Ri-ichiroh; Murata, Mitsuyoshi; Nagao-Sato, Sayaka; Nakazato, Kenichi; Ninomiya, Noriko; Nishiyori-Sueki, Hiromi; Noma, Shohei; Saijyo, Eri; Saka, Akiko; Sakai, Mizuho; Simon, Christophe; Suzuki, Naoko; Tagami, Michihira; Watanabe, Shoko; Yoshida, Shigehiro; Arner, Peter; Axton, Richard A.; Babina, Magda; Baillie, J. Kenneth; Barnett, Timothy C.; Beckhouse, Anthony G.; Blumenthal, Antje; Bodega, Beatrice; Bonetti, Alessandro; Briggs, James; Brombacher, Frank; Carlisle, Ailsa J.; Clevers, Hans C.; Davis, Carrie A.; Detmar, Michael; Dohi, Taeko; Edge, Albert S. B.; Edinger, Matthias; Ehrlund, Anna; Ekwall, Karl; Endoh, Mitsuhiro; Enomoto, Hideki; Eslami, Afsaneh; Fagiolini, Michela; Fairbairn, Lynsey; Farach-Carson, Mary C.; Faulkner, Geoffrey J.; Ferrai, Carmelo; Fisher, Malcolm E.; Forrester, Lesley M.; Fujita, Rie; Furusawa, Jun-ichi; Geijtenbeek, Teunis B.; Gingeras, Thomas; Goldowitz, Daniel; Guhl, Sven; Guler, Reto; Gustincich, Stefano; Ha, Thomas J.; Hamaguchi, Masahide; Hara, Mitsuko; Hasegawa, Yuki; Herlyn, Meenhard; Heutink, Peter; Hitchens, Kelly J.; Hume, David A.; Ikawa, Tomokatsu; Ishizu, Yuri; Kai, Chieko; Kawamoto, Hiroshi; Kawamura, Yuki I.; Kempfle, Judith S.; Kenna, Tony J.; Kere, Juha; Khachigian, Levon M.; Kitamura, Toshio; Klein, Sarah; Klinken, S. Peter; Knox, Alan J.; Kojima, Soichi; Koseki, Haruhiko; Koyasu, Shigeo; Lee, Weonju; Lennartsson, Andreas; Mackay-sim, Alan; Mejhert, Niklas; Mizuno, Yosuke; Morikawa, Hiromasa; Morimoto, Mitsuru; Moro, Kazuyo; Morris, Kelly J.; Motohashi, Hozumi; Mummery, Christine L.; Nakachi, Yutaka; Nakahara, Fumio; Nakamura, Toshiyuki; Nakamura, Yukio; Nozaki, Tadasuke; Ogishima, Soichi; Ohkura, Naganari; Ohno, Hiroshi; Ohshima, Mitsuhiro; Okada-Hatakeyama, Mariko; Okazaki, Yasushi; Orlando, Valerio; Ovchinnikov, Dmitry A.; Passier, Robert; Patrikakis, Margaret; Pombo, Ana; Pradhan-Bhatt, Swati; Qin, Xian-Yang; Rehli, Michael; Rizzu, Patrizia; Roy, Sugata; Sajantila, Antti; Sakaguchi, Shimon; Sato, Hiroki; Satoh, Hironori; Savvi, Suzana; Saxena, Alka; Schmidl, Christian; Schneider, Claudio; Schulze-Tanzil, Gundula G.; Schwegmann, Anita; Sheng, Guojun; Shin, Jay W.; Sugiyama, Daisuke; Sugiyama, Takaaki; Summers, Kim M.; Takahashi, Naoko; Takai, Jun; Tanaka, Hiroshi; Tatsukawa, Hideki; Tomoiu, Andru; Toyoda, Hiroo; van de Wetering, Marc; van den Berg, Linda M.; Verardo, Roberto; Vijayan, Dipti; Wells, Christine A.; Winteringham, Louise N.; Wolvetang, Ernst; Yamaguchi, Yoko; Yamamoto, Masayuki; Yanagi-Mizuochi, Chiyo; Yoneda, Misako; Yonekura, Yohei; Zhang, Peter G.; Zucchelli, Silvia; Abugessaisa, Imad; Arner, Erik; Harshbarger, Jayson; Kondo, Atsushi; Lassmann, Timo; Lizio, Marina; Sahin, Serkan; Sengstag, Thierry; Severin, Jessica; Shimoji, Hisashi; Suzuki, Masanori; Suzuki, Harukazu; Kawai, Jun; Kondo, Naoto; Itoh, Masayoshi; Daub, Carsten O.; Kasukawa, Takeya; Kawaji, Hideya; Carninci, Piero; Forrest, Alistair R. R.; Hayashizaki, Yoshihide (2017)
    In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.
  • Berta, Davide G.; Kuisma, Heli; Välimäki, Niko; Räisänen, Maritta; Jäntti, Maija; Pasanen, Annukka; Karhu, Auli; Kaukomaa, Jaana; Taira, Aurora; Cajuso, Tatiana; Nieminen, Sanna; Penttinen, Rosa-Maria; Ahonen, Saija; Lehtonen, Rainer; Mehine, Miika; Vahteristo, Pia; Jalkanen, Jyrki; Sahu, Biswajyoti; Ravantti, Janne; Mäkinen, Netta; Rajamäki, Kristiina; Palin, Kimmo; Taipale, Jussi; Heikinheimo, Oskari; Bützow, Ralf; Kaasinen, Eevi; Aaltonen, Lauri A. (2021)
    One in four women suffers from uterine leiomyomas (ULs)-benign tumours of the uterine wall, also known as uterine fibroids-at some point in premenopausal life. ULs can cause excessive bleeding, pain and infertility(1), and are a common cause of hysterectomy(2). They emerge through at least three distinct genetic drivers: mutations in MED12 or FH, or genomic rearrangement of HMGA2(3). Here we created genome-wide datasets, using DNA, RNA, assay for transposase-accessible chromatin (ATAC), chromatin immunoprecipitation (ChIP) and HiC chromatin immunoprecipitation (HiChIP) sequencing of primary tissues to profoundly understand the genesis of UL. We identified somatic mutations in genes encoding six members of the SRCAP histone-loading complex(4), and found that germline mutations in the SRCAP members YEATS4 and ZNHIT1 predispose women to UL. Tumours bearing these mutations showed defective deposition of the histone variant H2A.Z. In ULs, H2A.Z occupancy correlated positively with chromatin accessibility and gene expression, and negatively with DNA methylation, but these correlations were weak in tumours bearing SRCAP complex mutations. In these tumours, open chromatin emerged at transcription start sites where H2A.Z was lost, which was associated with upregulation of genes. Furthermore, YEATS4 defects were associated with abnormal upregulation of bivalent embryonic stem cell genes, as previously shown in mice(5). Our work describes a potential mechanism of tumorigenesis-epigenetic instability caused by deficient H2A.Z deposition-and suggests that ULs arise through an aberrant differentiation program driven by deranged chromatin, emanating from a small number of mutually exclusive driver mutations.
  • Seitsonen, Oula; Ikäheimo, Janne (2021)
    Open access airborne laser scanning (ALS) data have been available in Finland for over a decade and have been actively applied by the Finnish archaeologists in that time. The low resolution of this laser scanning 2008-2019 dataset (0.5 points/m(2)), however, has hindered its usability for archaeological prospection. In the summer of 2020, the situation changed markedly, when the Finnish National Land Survey started a new countrywide ALS survey with a higher resolution of 5 points/m(2). In this paper we present the first results of applying this newly available ALS material for archaeological studies. Finnish LIDARK consortium has initiated the development of semi-automated approaches for visualizing, detecting, and analyzing archaeological features with this new dataset. Our first case studies are situated in the Alpine tundra environment of Sapmi in northern Finland, and the assessed archaeological features range from prehistoric sites to indigenous Sami reindeer herding features and Second Word War-era German military structures. Already the initial analyses of the new ALS-5p data show their huge potential for locating, mapping, and assessing archaeological material. These results also suggest an imminent burst in the number of known archaeological sites, especially in the poorly accessible and little studied northern wilderness areas, when more data become available.
  • Rodriguez-Becerra, Jorge; Cáceres-Jensen, Lizethly; Díaz, Tatiana; Druker, Sofía; Bahamonde Padilla, Victor; Pernaa, Johannes; Aksela, Maija (2020)
    The purpose of this descriptive case study was to develop pre-service chemistry teachers’ Technological Pedagogical Science Knowledge (TPASK) through novel computational chemistry modules. The study consisted of two phases starting with designing a computational chemistry based learning environment followed by a case study where students’ perceptions towards educational computational chemistry were explored. First, we designed an authentic research-based chemistry learning module that supported problem-based learning through the utilization of computational chemistry methods suitable for pre-service chemistry education. The objective of the learning module was to promote learning of specific chemistry knowledge and development of scientific skills. Systematic design decisions were made through the TPASK framework. The learning module was designed for a third-year physical chemistry course taken by pre-service chemistry teachers in Chile. After the design phase, the learning module was implemented in a course and students’ perceptions were gathered using semi-structured group interviews. The sample consisted of 22 pre-service chemistry teachers. Data were analyzed through qualitative content analysis using the same TPASK framework employed in the learning module design. Based on our findings, pre-service chemistry teachers first acquired Technological Scientific Knowledge (TSK) and then developed some elements of their TPASK. In addition, they highly appreciated the combination of student-centred problem-based learning and the use of computational chemistry tools. Students felt the educational computational learning environment supported their own knowledge acquisition and expressed an interest in applying similar learning environments in their future teaching careers. This case study demonstrates that learning through authentic real-world problems using educational computational methods offers great potential in supporting pre-service teachers’ instruction in the science of chemistry and pedagogy. For further research in the TPASK framework, we propose there would be significant benefit from developing additional learning environments of this nature and evaluating their utility in pre-service and in-service chemistry teacher’s education.
  • Katainen, Riku; Donner, Iikki; Cajuso, Tatiana; Kaasinen, Eevi; Palin, Kimmo; Mäkinen, Veli; Aaltonen, Lauri A.; Pitkänen, Esa (2018)
    Next-generation sequencing (NGS) is routinely applied in life sciences and clinical practice, but interpretation of the massive quantities of genomic data produced has become a critical challenge. The genome-wide mutation analyses enabled by NGS have had a revolutionary impact in revealing the predisposing and driving DNA alterations behind a multitude of disorders. The workflow to identify causative mutations from NGS data, for example in cancer and rare diseases, commonly involves phases such as quality filtering, case-control comparison, genome annotation, and visual validation, which require multiple processing steps and usage of various tools and scripts. To this end, we have introduced an interactive and user-friendly multi-platform-compatible software, BasePlayer, which allows scientists, regardless of bioinformatics training, to carry out variant analysis in disease genetics settings. A genome-wide scan of regulatory regions for mutation clusters can be carried out with a desktop computer in -10 min with a dataset of 3 million somatic variants in 200 whole-genome-sequenced (WGS) cancers.
  • Palviainen, Mari; Saraswat, Mayan K.; Varga, Zoltan; Kitka, Diana; Neuvonen, Maarit; Puhka, Maija; Joenväärä, Sakari; Renkonen, Risto; Nieuwland, Rienk; Takatalo, Maarit; Siljander, Pia R. M. (2020)
    Extracellular vesicles (EVs) in human blood are a potential source of biomarkers. To which extent anticoagulation affects their concentration, cellular origin and protein composition is largely unexplored. To study this, blood from 23 healthy subjects was collected in acid citrate dextrose (ACD), citrate or EDTA, or without anticoagulation to obtain serum. EVs were isolated by ultracentrifugation or by size-exclusion chromatography (SEC) for fluorescence-SEC. EVs were analyzed by micro flow cytometry, NTA, TEM, Western blot, and protein mass spectrometry. The plasma EV concentration was unaffected by anticoagulants, but serum contained more platelet EVs. The protein composition of plasma EVs differed between anticoagulants, and between plasma and serum. Comparison to other studies further revealed that the shared EV protein composition resembles the "protein corona" of synthetic nanoparticles incubated in plasma or serum. In conclusion, we have validated a higher concentration of platelet EVs in serum than plasma by contemporary EV methods. Anticoagulation should be carefully described (i) to enable study comparison, (ii) to utilize available sample cohorts, and (iii) when preparing/selecting biobank samples. Further, the similarity of the EV protein corona and that of nanoparticles implicates that EVs carry both intravesicular and extravesicular cargo, which will expand their applicability for biomarker discovery.
  • Revez, Joana; Llarena, Ann-Katrin; Schott, Thomas; Kuusi, Markku; Hakkinen, Marjaana; Kivistö, Rauni; Hänninen, Marja-Liisa; Rossi, Mirko (2014)
  • Einarsdottir, Elisabet; Hafren, Lena; Leinonen, Eira; Bhutta, Mahmood F.; Kentala, Erna; Kere, Juha; Mattila, Petri S. (2016)
    To identify genetic risk factors of childhood otitis media (OM), a genome-wide association study was performed on Finnish subjects, 829 affected children, and 2118 randomly selected controls. The most significant and validated finding was an association with an 80 kb region on chromosome 19. It includes the variants rs16974263 (P = 1.77 x 10(-7), OR = 1.59), rs268662 (P = 1.564 x 10(-6), OR = 1.54), and rs4150992 (P = 3.37 x 10(-6), OR = 1.52), and harbors the genes PLD3, SERTAD1, SERTAD3, HIPK4, PRX, and BLVRB, all in strong linkage disequilibrium. In a sub-phenotype analysis of the 512 patients with chronic otitis media with effusion, one marker reached genome-wide significance (rs16974263, P = 2.92 x 10(-8)). The association to this locus was confirmed but with an association signal in the opposite direction, in a UK family cohort of 4860 subjects (rs16974263, P = 3.21 x 10(-4), OR = 0.72; rs4150992, P = 1.62 x 10(-4), OR = 0.71). Thus we hypothesize that this region is important for COME risk in both the Finnish and UK populations, although the precise risk variants or haplotype background remain unclear. Our study suggests that the identified region on chromosome 19 includes a novel and previously uncharacterized risk locus for OM.
  • Pölönen, Petri; Mehtonen, Juha; Lin, Jake; Liuksiala, Thomas; Häyrynen, Sergei; Teppo, Susanna; Mäkinen, Artturi; Kumar, Ashwini; Malani, Disha; Pohjolainen, Virva; Porkka, Kimmo; Heckman, Caroline A.; May, Patrick; Hautamäki, Ville; Granberg, Kirsi J.; Lohi, Olli; Nykter, Matti; Heinäniemi, Merja (2019)
    Large collections of genome-wide data can facilitate the characterization of disease states and subtypes, permitting pan-cancer analysis of molecular phenotypes and evaluation of disease context for new therapeutic approaches. We analyzed 9,544 transcriptomes from more than 30 hematologic malignancies, normal blood cell types, and cell lines, and showed that disease types could be stratified in a data-driven manner. We then identified cluster-specific pathway activity, new biomarkers, and in silico drug target prioritization through interrogation of drug target databases. Using known vulnerabilities and available drug screens, we highlighted the importance of integrating molecular phenotype with drug target expression for in silico prediction of drug responsiveness. Our analysis implicated BCL2 expression level as an important indicator of venetoclax responsiveness and provided a rationale for its targeting in specific leukemia subtypes and multiple myeloma, linked several polycomb group proteins that could be targeted by small molecules (SFMBT1, CBX7, and EZH1) with chronic lymphocytic leukemia, and supported CDK6 as a disease-specific target in acute myeloid leukemia. Through integration with proteomics data, we characterized target protein expression for pre-B leukemia immunotherapy candidates, including DPEP1. These molecular data can be explored using our publicly available interactive resource, Hemap, for expediting therapeutic innovations in hematologic malignancies.
  • Parey, Kristian; Lasham, Jonathan; Mills, Deryck J.; Djurabekova, Amina; Haapanen, Outi; Yoga, Etienne Galemou; Xie, Hao; Kuhlbrandt, Werner; Sharma, Vivek; Vonck, Janet; Zickermann, Volker (2021)
    Mitochondrial NADH:ubiquinone oxidoreductase (complex I) is a 1-MDa membrane protein complex with a central role in energy metabolism. Redox-driven proton translocation by complex I contributes substantially to the proton motive force that drives ATP synthase. Several structures of complex I from bacteria and mitochondria have been determined, but its catalytic mechanism has remained controversial. We here present the cryo-EM structure of complex I from Yarrowia lipolytica at 2.1-angstrom resolution, which reveals the positions of more than 1600 protein-bound water molecules, of which similar to 100 are located in putative proton translocation pathways. Another structure of the same complex under steady-state activity conditions at 3.4-angstrom resolution indicates conformational transitions that we associate with proton injection into the central hydrophilic axis. By combining high-resolution structural data with site-directed mutagenesis and large-scale molecular dynamic simulations, we define details of the proton translocation pathways and offer insights into the redox-coupled proton pumping mechanism of complex I.
  • Koskinen, Lotta L. E.; Seppälä, Eija H.; Belanger, Janelle M.; Arumilli, Meharji; Hakosalo, Osmo; Jokinen, Paivi; Nevalainen, Elisa M.; Viitmaa, Ranno; Jokinen, Tarja S.; Oberbauer, Anita M.; Lohi, Hannes (2015)
    Background: Idiopathic epilepsy is a common neurological disease in human and domestic dogs but relatively few risk genes have been identified to date. The seizure characteristics, including focal and generalised seizures, are similar between the two species, with gene discovery facilitated by the reduced genetic heterogeneity of purebred dogs. We have recently identified a risk locus for idiopathic epilepsy in the Belgian Shepherd breed on a 4.4 megabase region on CFA37. Results: We have expanded a previous study replicating the association with a combined analysis of 157 cases and 179 controls in three additional breeds: Schipperke, Finnish Spitz and Beagle (p(c) = 2.9e-07, p(GWAS) = 1.74E-02). A targeted resequencing of the 4.4 megabase region in twelve Belgian Shepherd cases and twelve controls with opposite haplotypes identified 37 case-specific variants within the ADAM23 gene. Twenty-seven variants were validated in 285 cases and 355 controls from four breeds, resulting in a strong replication of the ADAM23 locus (p(raw) = 2.76e-15) and the identification of a common 28 kb-risk haplotype in all four breeds. Risk haplotype was present in frequencies of 0.49-0.7 in the breeds, suggesting that ADAM23 is a low penetrance risk gene for canine epilepsy. Conclusions: These results implicate ADAM23 in common canine idiopathic epilepsy, although the causative variant remains yet to be identified. ADAM23 plays a role in synaptic transmission and interacts with known epilepsy genes, LGI1 and LGI2, and should be considered as a candidate gene for human epilepsies.