Browsing by Subject "DATABASE"

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  • Fondi, Marco; Karkman, Antti; Tamminen, Manu V.; Bosi, Emanuele; Virta, Marko; Fani, Renato; Alm, Eric; McInerney, James O. (2016)
    The spatial distribution of microbes on our planet is famously formulated in the Baas Becking hypothesis as everything is everywhere but the environment selects." While this hypothesis does not strictly rule out patterns caused by geographical effects on ecology and historical founder effects, it does propose that the remarkable dispersal potential of microbes leads to distributions generally shaped by environmental factors rather than geographical distance. By constructing sequence similarity networks from uncultured environmental samples, we show that microbial gene pool distributions are not influenced nearly as much by geography as ecology, thus extending the Bass Becking hypothesis from whole organisms to microbial genes. We find that gene pools are shaped by their broad ecological niche (such as sea water, fresh water, host, and airborne). We find that freshwater habitats act as a gene exchange bridge between otherwise disconnected habitats. Finally, certain antibiotic resistance genes deviate from the general trend of habitat specificity by exhibiting a high degree of cross-habitat mobility. The strong cross-habitat mobility of antibiotic resistance genes is a cause for concern and provides a paradigmatic example of the rate by which genes colonize new habitats when new selective forces emerge.
  • Golub, Malgorzata; Thiery, Wim; Marce, Rafael; Pierson, Don; Vanderkelen, Inne; Mercado-Bettin, Daniel; Woolway, R. Iestyn; Grant, Luke; Jennings, Eleanor; Kraemer, Benjamin M.; Schewe, Jacob; Zhao, Fang; Frieler, Katja; Mengel, Matthias; Bogomolov, Vasiliy Y.; Bouffard, Damien; Cote, Marianne; Couture, Raoul-Marie; Debolskiy, Andrey; Droppers, Bram; Gal, Gideon; Guo, Mingyang; Janssen, Annette B. G.; Kirillin, Georgiy; Ladwig, Robert; Magee, Madeline; Moore, Tadhg; Perroud, Marjorie; Piccolroaz, Sebastiano; Vinnaa, Love Raaman; Schmid, Martin; Shatwell, Tom; Stepanenko, Victor M.; Tan, Zeli; Woodward, Bronwyn; Yao, Huaxia; Adrian, Rita; Allan, Mathew; Anneville, Orlane; Arvola, Lauri; Atkins, Karen; Boegman, Leon; Carey, Cayelan; Christianson, Kyle; de Eyto, Elvira; DeGasperi, Curtis; Grechushnikova, Maria; Hejzlar, Josef; Joehnk, Klaus; Jones, Ian D.; Laas, Alo; Mackay, Eleanor B.; Mammarella, Ivan; Markensten, Hampus; McBride, Chris; Ozkundakci, Deniz; Potes, Miguel; Rinke, Karsten; Robertson, Dale; Rusak, James A.; Salgado, Rui; van der Linden, Leon; Verburg, Piet; Wain, Danielle; Ward, Nicole K.; Wollrab, Sabine; Zdorovennova, Galina (2022)
    Empirical evidence demonstrates that lakes and reservoirs are warming across the globe. Consequently, there is an increased need to project future changes in lake thermal structure and resulting changes in lake biogeochemistry in order to plan for the likely impacts. Previous studies of the impacts of climate change on lakes have often relied on a single model forced with limited scenario-driven projections of future climate for a relatively small number of lakes. As a result, our understanding of the effects of climate change on lakes is fragmentary, based on scattered studies using different data sources and modelling protocols, and mainly focused on individual lakes or lake regions. This has precluded identification of the main impacts of climate change on lakes at global and regional scales and has likely contributed to the lack of lake water quality considerations in policy-relevant documents, such as the Assessment Reports of the Intergovernmental Panel on Climate Change (IPCC). Here, we describe a simulation protocol developed by the Lake Sector of the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP) for simulating climate change impacts on lakes using an ensemble of lake models and climate change scenarios for ISIMIP phases 2 and 3. The protocol prescribes lake simulations driven by climate forcing from gridded observations and different Earth system models under various representative greenhouse gas concentration pathways (RCPs), all consistently bias-corrected on a 0.5 degrees x 0.5 degrees global grid. In ISIMIP phase 2, 11 lake models were forced with these data to project the thermal structure of 62 well-studied lakes where data were available for calibration under historical conditions, and using uncalibrated models for 17 500 lakes defined for all global grid cells containing lakes. In ISIMIP phase 3, this approach was expanded to consider more lakes, more models, and more processes. The ISIMIP Lake Sector is the largest international effort to project future water temperature, thermal structure, and ice phenology of lakes at local and global scales and paves the way for future simulations of the impacts of climate change on water quality and biogeochemistry in lakes.
  • Bodea, Corneliu A.; Neale, Benjamin M.; Ripke, Stephan; Daly, Mark J.; Devlin, Bernie; Roeder, Kathryn; Int IBD Genetics Consortium; Palotie, A. (2016)
    One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.
  • Su, Jing; Ekman, Carl; Oskolkov, Nikolay; Lahti, Leo; Ström, Kristoffer; Brazma, Alvis; Groop, Leif; Rung, Johan; Hansson, Ola (2015)
    Background: Although high-throughput studies of gene expression have generated large amounts of data, most of which is freely available in public archives, the use of this valuable resource is limited by computational complications and non-homogenous annotation. To address these issues, we have performed a complete re-annotation of public microarray data from human skeletal muscle biopsies and constructed a muscle expression compendium consisting of nearly 3000 samples. The created muscle compendium is a publicly available resource including all curated annotation. Using this data set, we aimed to elucidate the molecular mechanism of muscle aging and to describe how physical exercise may alleviate negative physiological effects. Results: We find 957 genes to be significantly associated with aging (p <0.05, FDR = 5 %, n = 361). Aging was associated with perturbation of many central metabolic pathways like mitochondrial function including reduced expression of genes in the ATP synthase, NADH dehydrogenase, cytochrome C reductase and oxidase complexes, as well as in glucose and pyruvate processing. Among the genes with the strongest association with aging were H3 histone, family 3B (H3F3B, p = 3.4 x 10(-13)), AHNAK nucleoprotein, desmoyokin (AHNAK, p = 6.9 x 10(-12)), and histone deacetylase 4 (HDAC4, p = 4.0 x 10(-9)). We also discover genes previously not linked to muscle aging and metabolism, such as fasciculation and elongation protein zeta 2 (FEZ2, p = 2.8 x 10(-8)). Out of the 957 genes associated with aging, 21 (p <0.001, false discovery rate = 5 %, n = 116) were also associated with maximal oxygen consumption (VO2MAX). Strikingly, 20 out of those 21 genes are regulated in opposite direction when comparing increasing age with increasing VO2MAX. Conclusions: These results support that mitochondrial dysfunction is a major age-related factor and also highlight the beneficial effects of maintaining a high physical capacity for prevention of age-related sarcopenia.
  • Kaukonen, Maria; Quintero, Ileana B.; Mukarram, Abdul Kadir; Hytönen, Marjo K.; Holopainen, Saila; Wickström, Kaisa; Kyöstilä, Kaisa; Arumilli, Meharji; Jalomäki, Sari; Daub, Carsten O.; Kere, Juha; Lohi, Hannes; Consortium, the DoGA (2020)
    Author summary Retinitis pigmentosa (RP) is a blinding eye disease that affects nearly two million people worldwide. Several genes and variants have been associated with the disease, but still 30-80% of the patients lack genetic diagnosis. There is currently no standard treatment for RP, and much is expected from gene therapy. A similar disease, called progressive retinal atrophy (PRA), affects many dog breeds. We performed clinical, genetic and functional analyses to find the genetic cause for PRA in Miniature Schnauzers. We discovered two forms of PRA in the breed, named type 1 and 2, and show that they are genetically distinct as they map to different chromosomes, 15 and X, respectively. Further genetic, bioinformatic and functional analyses discovered a fully penetrant recessive variant in a putative silencer region for type 1 PRA. Silencer regions are important for gene regulation and we found that two of its predicted target genes, EDN2 and COL9A2, were overexpressed in the retina of the affected dog. Defects in both EDN2 and COL9A2 have been associated with retinal degeneration. This study provides new insights to retinal biology while the genetic test guides better breeding choices. Retinitis pigmentosa (RP) is the leading cause of blindness with nearly two million people affected worldwide. Many genes have been implicated in RP, yet in 30-80% of the RP patients the genetic cause remains unknown. A similar phenotype, progressive retinal atrophy (PRA), affects many dog breeds including the Miniature Schnauzer. We performed clinical, genetic and functional experiments to identify the genetic cause of PRA in the breed. The age of onset and pattern of disease progression suggested that at least two forms of PRA, types 1 and 2 respectively, affect the breed, which was confirmed by genome-wide association study that implicated two distinct genomic loci in chromosomes 15 and X, respectively. Whole-genome sequencing revealed a fully segregating recessive regulatory variant in type 1 PRA. The associated variant has a very recent origin based on haplotype analysis and lies within a regulatory site with the predicted binding site of HAND1::TCF3 transcription factor complex. Luciferase assays suggested that mutated regulatory sequence increases expression. Case-control retinal expression comparison of six best HAND1::TCF3 target genes were analyzed with quantitative reverse-transcriptase PCR assay and indicated overexpression of EDN2 and COL9A2 in the affected retina. Defects in both EDN2 and COL9A2 have been previously associated with retinal degeneration. In summary, our study describes two genetically different forms of PRA and identifies a fully penetrant variant in type 1 form with a possible regulatory effect. This would be among the first reports of a regulatory variant in retinal degeneration in any species, and establishes a new spontaneous dog model to improve our understanding of retinal biology and gene regulation while the affected breed will benefit from a reliable genetic testing.
  • Chichorro, Filipe; Juslén, Aino; Cardoso, Pedro (2019)
    Biodiversity is shrinking rapidly, and despite our efforts only a small part of it has been assessed for extinction risk. Identifying the traits that make species vulnerable might help us to predict the status for those less known. We gathered information on the relationships between traits and extinction risk from 173 publications, across all taxa, spatial scales and biogeographical regions, in what we think it is the most comprehensive compilation to date. We aimed to identify (1) taxonomical and spatial biases, and (2) statistically robust and generalizable predictors of extinction risk through the use of meta-analyses. Vertebrates and the Palaearctic are the most studied taxon and region because of higher accumulation of data in these groups. Among the many traits that have been suggested to be predictors, only three had enough data for meta-analyses. Two of them are potentially useful in assessing risk for the lesser-known species: regardless of the taxon, species with small range and narrow habitat breadth are more vulnerable to extinction. Contrastingly, body size (the most studied trait) did not present a consistently positive or negative response. We hypothesize that the relationship between body size and extinction risk is shaped by different aspects, namely the phenomena represented by body size depending on the taxonomic group. To increase our understanding of the drivers of extinction, further studies should focus on understudied groups such as invertebrates and fungi and regions such as the tropics and expand the number of traits in comparative analyses that should avoid current biases.
  • Early Growth Genetics Consortium; Bradfield, Jonathan P.; Vogelezang, Suzanne; Pitkänen, Niina; Leinonen, Jaakko T.; Lindi, Virpi; Atalay, Mustafa; Kähönen, Mika; Raitakari, Olli T.; Eriksson, Johan; Widen, Elisabeth (2019)
    Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13005 cases (>= 95th percentile of body mass index (BMI) achieved 2-18 years old) and 15599 controls (consistently
  • Jones, W; Gong, BS; Novoradovskaya, N; Li, D; Kusko, R; Richmond, TA; Johann, DJ; Bisgin, H; Sahraeian, SME; Bushel, PR; Pirooznia, M; Wilkins, K; Chierici, M; Bao, WJ; Basehore, LS; Lucas, AB; Burgess, D; Butler, DJ; Cawley, S; Chang, CJ; Chen, GC; Chen, T; Chen, YC; Craig, DJ; Del Pozo, A; Foox, J; Francescatto, M; Fu, YT; Furlanello, C; Giorda, K; Grist, KP; Guan, MJ; Hao, YY; Happe, S; Hariani, G; Haseley, N; Jasper, J; Jurman, G; Kreil, DP; Labaj, P; Lai, K; Li, JY; Li, QZ; Li, YL; Li, ZG; Liu, ZC; Lopez, MS; Miclaus, K; Miller, R; Mittal, VK; Mohiyuddin, M; Pabon-Pena, C; Parsons, BL; Qiu, FJ; Scherer, A; Shi, TL; Stiegelmeyer, S; Suo, C; Tom, N; Wang, D; Wen, ZN; Wu, LH; Xiao, WZ; Xu, C; Yu, Y; Zhang, JY; Zhang, YF; Zhang, ZH; Zheng, YT; Mason, CE; Willey, JC; Tong, WD; Shi, LM; Xu, J (2021)
    BackgroundOncopanel genomic testing, which identifies important somatic variants, is increasingly common in medical practice and especially in clinical trials. Currently, there is a paucity of reliable genomic reference samples having a suitably large number of pre-identified variants for properly assessing oncopanel assay analytical quality and performance. The FDA-led Sequencing and Quality Control Phase 2 (SEQC2) consortium analyze ten diverse cancer cell lines individually and their pool, termed Sample A, to develop a reference sample with suitably large numbers of coding positions with known (variant) positives and negatives for properly evaluating oncopanel analytical performance.ResultsIn reference Sample A, we identify more than 40,000 variants down to 1% allele frequency with more than 25,000 variants having less than 20% allele frequency with 1653 variants in COSMIC-related genes. This is 5-100x more than existing commercially available samples. We also identify an unprecedented number of negative positions in coding regions, allowing statistical rigor in assessing limit-of-detection, sensitivity, and precision. Over 300 loci are randomly selected and independently verified via droplet digital PCR with 100% concordance. Agilent normal reference Sample B can be admixed with Sample A to create new samples with a similar number of known variants at much lower allele frequency than what exists in Sample A natively, including known variants having allele frequency of 0.02%, a range suitable for assessing liquid biopsy panels.ConclusionThese new reference samples and their admixtures provide superior capability for performing oncopanel quality control, analytical accuracy, and validation for small to large oncopanels and liquid biopsy assays.
  • Hsu, Shih-Ying; Liu, Sheng-Yuan; Liu, Tie; Sahu, Dipen; Hirano, Naomi; Lee, Chin-Fei; Tatematsu, Ken'ichi; Kim, Gwanjeong; Juvela, Mika; Sanhueza, Patricio; He, Jinhua; Johnstone, Doug; Qin, Sheng-Li; Bronfman, Leonardo; Chen, Huei-Ru Vivien; Dutta, Somnath; Eden, David J.; Jhan, Kai-Syun; Kim, Kee-Tae; Kuan, Yi-Jehng; Kwon, Woojin; Lee, Chang Won; Lee, Jeong-Eun; Moraghan, Anthony; Rawlings, M. G.; Shang, Hsien; Soam, Archana; Thompson, M. A.; Traficante, Alessio; Wu, Yuefang; Yang, Yao-Lun; Zhang, Qizhou (2020)
    We report the detection of four new hot corino sources, G211.47-19.27S, G208.68-19.20N1, G210.49-19.79W, and G192.12-11.10, from a survey study of Planck Galactic Cold Clumps in the Orion Molecular Cloud Complex with the Atacama Compact Array. Three sources had been identified as low-mass Class 0 protostars in the Herschel Orion Protostar Survey. One source in the lambda Orionis region is first reported as a protostellar core. We have observed abundant complex organic molecules (COMs), primarily methanol but also other oxygen-bearing COMs (in G211.47-19.27S and G208.68-19.20N1) and the molecule of prebiotic interest NH2CHO (in G211.47-19.27S), signifying the presence of hot corinos. While our spatial resolution is not sufficient to resolve most of the molecular emission structure, the large line width and high rotational temperature of COMs suggest that they likely reside in the hotter and innermost region immediately surrounding the protostar. In G211.47-19.27S, the D/H ratio of methanol ([CH2DOH]/[CH3OH]) and the(12)C/C-13 ratio of methanol ([CH3OH]/[(CH3OH)-C-13]) are comparable to those of other hot corinos. Hydrocarbons and long-carbon-chain molecules such as c-C(3)H(2)and HCCCN are also detected in the four sources, likely tracing the outer and cooler molecular envelopes.
  • Rooijers, Koos; Kolmeder, Carolin; Juste, Catherine; Dore, Joel; de Been, Mark; Boeren, Sjef; Galan, Pilar; Beauvallet, Christian; de Vos, Willem M.; Schaap, Peter J. (2011)
  • Kankainen, Matti; Ojala, Teija; Holm, Liisa (2012)
  • Lu, Jiaheng; Lin, Chunbin; Wang, Wei; Li, Chen; Xiao, Xiaokui (2015)
    A string similarity measure quantifies the similarity between two text strings for approximate string matching or comparison. For example, the strings ``\textsf{Sam}'' and ``\textsf{Samuel}'' can be considered to be similar. Most existing work that computes the similarity of two strings only considers syntactic similarities, e.g., number of common words or \qgrams. While this is indeed an indicator of similarity, there are many important cases where syntactically different strings can represent the same real-world object. For example, ``\textsf{Bill}'' is a short form of ``\textsf{William}''; and ``\textsf{Database Management Systems}'' can be abbreviated as ``\textsf{DBMS}''. Given a collection of predefined synonyms, the purpose of this article is to explore such existing knowledge to effectively evaluate the similarity between two strings and efficiently perform similarity searches and joins, thereby boosting the quality of approximate string matching. In particular, we first present an expansion-based framework to measure string similarities efficiently while considering synonyms. We then study efficient algorithms for similarity searches and joins by proposing two novel indexes, called SI-tree and QP-tree, which combine signature filtering and length filtering strategies. In order to improve the efficiency of our algorithms, we develop an estimator to estimate the size of candidates to enable an online selection of signature filters. This estimator provides strong low-error, high-confidence guarantees while requiring only logarithmic space and time costs, thus making our method attractive both in theory and in practice. Finally, the experimental results from a comprehensive study of the algorithms with three real datasets verify the effectiveness and efficiency of our approaches.
  • Zheng, Guoqiao; Catalano, Calogerina; Bandapalli, Obul Reddy; Paramasivam, Nagarajan; Chattopadhyay, Subhayan; Schlesner, Matthias; Sijmons, Rolf; Hemminki, Akseli; Dymerska, Dagmara; Lubinski, Jan; Hemminki, Kari; Försti, Asta (2020)
    Simple Summary Familial clustering of cancer and identification of high- and low-risk cancer predisposition gene variants implicate that there are families that are at a high to moderate excess risk of cancer. We wanted to test genetically whether there are families protected from cancer. We whole-genome sequenced 51 elderly individuals without any personal or family history of cancer. We identified less high-risk loss-of-function variants in known and suggested cancer predisposition genes in these cancer-free individuals than in the general population. However, our results for low-risk variants were not conclusive. Our study suggests that random environmental causes of cancer are so dominant that a clear demarcation of cancer-free populations using genetic data may not be feasible. However, carrier identification of and counseling about prevalent high-risk cancer predisposition genes is useful. Familial clustering, twin concordance, and identification of high- and low-penetrance cancer predisposition variants support the idea that there are families that are at a high to moderate excess risk of cancer. To what extent there may be families that are protected from cancer is unknown. We wanted to test genetically whether cancer-free families share fewer breast, colorectal, and prostate cancer risk alleles than the population at large. We addressed this question by whole-genome sequencing (WGS) of 51 elderly cancer-free individuals whose numerous (ca. 1000) family members were found to be cancer-free ('cancer-free families', CFFs) based on face-to-face interviews. The average coverage of the 51 samples in the WGS was 42x. We compared cancer risk allele frequencies in cancer-free individuals with those in the general population available in public databases. The CFF members had fewer loss-of-function variants in suggested cancer predisposition genes compared to the ExAC data, and for high-risk cancer predisposition genes, no pathogenic variants were found in CFFs. For common low-penetrance breast, colorectal, and prostate cancer risk alleles, the results were not conclusive. The results suggest that, in line with twin and family studies, random environmental causes are so dominant that a clear demarcation of cancer-free populations using genetic data may not be feasible.
  • Eichin, Dominik; Pessia, Alberto; Takeda, Akira; Laakkonen, Joni; Bellmann, Lydia; Kankainen, Matti; Imhof, Beat A.; Stoitzner, Patrizia; Tang, Jing; Salmi, Marko; Jalkanen, Sirpa (2021)
    CD73 is an important ectoenzyme responsible for the production of extracellular adenosine. It is involved in regulating inflammatory responses and cell migration and is overexpressed in various cancers. The functions of CD73 in blood endothelial cells are understood in detail, but its role on afferent lymphatics remains unknown. Moreover, anti‐CD73 antibodies are now used in multiple clinical cancer trials, but their effects on different endothelial cell types have not been studied. This study reveals that a previously unknown role of CD73 on afferent lymphatics is to dampen immune responses. Knocking it out or suppressing it by siRNA leads to the upregulation of inflammation‐associated genes on lymphatic endothelial cells and a more pro‐inflammatory phenotype of interacting dendritic cells in vitro and in vivo. In striking contrast, anti‐CD73 antibodies had only negligible effects on the gene expression of lymphatic‐ and blood‐endothelial cells. Our data thus reveal new functions of lymphatic CD73 and indicate a low likelihood of endothelial cell–related adverse effects by CD73 targeting therapeutic antibodies.
  • Yli-Kyyny, Tero; Sund, Reijo; Heinanen, Mikko; Venesmaa, Petri; Kroger, Heikki (2014)
  • Daly, Paul; Peng, Mao; Mitchell, Hugh D.; Kim, Young-Mo; Ansong, Charles; Brewer, Heather; de Gijsel, Peter; Lipton, Mary S.; Markillie, Lye Meng; Nicora, Carrie D.; Orr, Galya; Wiebenga, Ad; Hilden, Kristiina S.; Kabel, Mirjam A.; Baker, Scott E.; Makela, Miia R.; de Vries, Ronald P. (2020)
    Saprobic fungi, such as Aspergillus niger, grow as colonies consisting of a network of branching and fusing hyphae that are often considered to be relatively uniform entities in which nutrients can freely move through the hyphae. In nature, different parts of a colony are often exposed to different nutrients. We have investigated, using a multi-omics approach, adaptation of A. niger colonies to spatially separated and compositionally different plant biomass substrates. This demonstrated a high level of intra-colony differentiation, which closely matched the locally available substrate. The part of the colony exposed to pectin-rich sugar beet pulp and to xylan-rich wheat bran showed high pectinolytic and high xylanolytic transcript and protein levels respectively. This study therefore exemplifies the high ability of fungal colonies to differentiate and adapt to local conditions, ensuring efficient use of the available nutrients, rather than maintaining a uniform physiology throughout the colony.
  • Miyauchi, Shingo; Hage, Hayat; Drula, Elodie; Lesage-Meessen, Laurence; Berrin, Jean-Guy; Navarro, David; Favel, Anne; Chaduli, Delphine; Grisel, Sacha; Haon, Mireille; Piumi, Francois; Levasseur, Anthony; Lomascolo, Anne; Ahrendt, Steven; Barry, Kerrie; LaButti, Kurt M.; Chevret, Didier; Daum, Chris; Mariette, Jerome; Klopp, Christophe; Cullen, Daniel; de Vries, Ronald P.; Gathman, Allen C.; Hainaut, Matthieu; Henrissat, Bernard; Hilden, Kristiina S.; Kuees, Ursula; Lilly, Walt; Lipzen, Anna; Maekelae, Miia R.; Martinez, Angel T.; Morel-Rouhier, Melanie; Morin, Emmanuelle; Pangilinan, Jasmyn; Ram, Arthur F. J.; Woesten, Han A. B.; Ruiz-Duenas, Francisco J.; Riley, Robert; Record, Eric; Grigoriev, Igor; Rosso, Marie-Noelle (2020)
    White-rot (WR) fungi are pivotal decomposers of dead organic matter in forest ecosystems and typically use a large array of hydrolytic and oxidative enzymes to deconstruct lignocellulose. However, the extent of lignin and cellulose degradation may vary between species and wood type. Here, we combined comparative genomics, transcriptomics and secretome proteomics to identify conserved enzymatic signatures at the onset of wood-decaying activity within the Basidiomycota genus Pycnoporus. We observed a strong conservation in the genome structures and the repertoires of protein-coding genes across the four Pycnoporus species described to date, despite the species having distinct geographic distributions. We further analysed the early response of P. cinnabarinus, P. coccineus and P. sanguineus to diverse (ligno)-cellulosic substrates. We identified a conserved set of enzymes mobilized by the three species for breaking down cellulose, hemicellulose and pectin. The co-occurrence in the exo-proteomes of H2O2-producing enzymes with H2O2-consuming enzymes was a common feature of the three species, although each enzymatic partner displayed independent transcriptional regulation. Finally, cellobiose dehydrogenase-coding genes were systematically co-regulated with at least one AA9 lytic polysaccharide monooxygenase gene, indicative of enzymatic synergy in vivo. This study highlights a conserved core white-rot fungal enzymatic mechanism behind the wood-decaying process.
  • Toivo, Terhi; Dimitrow, Maarit; Puustinen, Juha; Savela, Eeva; Pelkonen, Katariina; Kiuru, Valtteri; Suominen, Tuula; Kinnunen, Sirkka; Uunimäki, Mira; Kivelä, Sirkka-Liisa; Leikola, Saija; Airaksinen, Marja (2018)
    Background: The magnitude of safety risks related to medications of the older adults has been evidenced by numerous studies, but less is known of how to manage and prevent these risks in different health care settings. The aim of this study was to coordinate resources for prospective medication risk management of home care clients >= 65 years in primary care and to develop a study design for demonstrating effectiveness of the procedure. Methods: Health care units involved in the study are from primary care in Lohja, Southern Finland: home care (191 consented clients), the public healthcare center, and a private community pharmacy. System based risk management theory and action research method was applied to construct the collaborative procedure utilizing each profession's existing resources in medication risk management of older home care clients. An inventory of clinical measures in usual clinical practice and systematic review of rigorous study designs was utilized in effectiveness study design. Discussion: The new coordinated medication management model (CoMM) has the following 5 stages: 1) practical nurses are trained to identify clinically significant drug-related problems (DRPs) during home visits and report those to the clinical pharmacist. Clinical pharmacist prepares the cases for 2) an interprofessional triage meeting (50-70 cases/meeting of 2 h) where decisions are made on further action, e.g., more detailed medication reviews, 3) community pharmacists conduct necessary medication reviews and each patients' physician makes final decisions on medication changes needed. The final stages concern 4) implementation and 5) follow-up of medication changes. Randomized controlled trial (RCT) was developed to demonstrate the effectiveness of the procedure. The developed procedure is feasible for screening and reviewing medications of a high number of older home care clients to identify clients with severe DRPs and provide interventions to solve them utilizing existing primary care resources.
  • DDD Study; Konrad, Enrico D. H.; Nardini, Niels; Kuismin, Outi; Kurki, Mitja I.; Pietiläinen, Olli; Palotie, Aarno (2019)
    Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum of CTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.