Reduced natriuretic response to acute sodium loading in COMT Gene deleted mice

BACKGROUND: The intrarenal natriuretic hormone dopamine (DA) is metabolised by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). Inhibition of COMT, as opposed to MAO, results in a potent natriuretic response in the rat. The present study in anaesthetized homozygous and heterozygous COMT gene deleted mice attempted to further elucidate the importance of COMT in renal DA and sodium handling. After acute intravenous isotonic sodium loading, renal function was followed. RESULTS: COMT activity in heterozygous mice was about half of that in wild type mice and was zero in the homozygous mice. MAO activity did not differ between the genotypes. Urinary sodium excretion increased 10-fold after sodium loading in wild type mice. In heterozygous and homozygous mice, the natriuretic effects of sodium loading were only 29 % and 39 %, respectively, of that in wild type mice. Arterial pressure and glomerular filtration rate did not differ between genotypes. Baseline norepinephrine and DA excretions in urine were elevated in the homozygous, but not in heterozygous, COMT gene deleted mice. Urinary DA excretion increased after isotonic sodium loading in the wild type mice but not in the COMT gene deleted mice. CONCLUSIONS: Mice with reduced or absent COMT activity have altered metabolism of catecholamines and are unable to increase renal DA activity and produce normal natriuresis in response to acute sodium loading. The results support the hypothesis that COMT has an important role in the DA-mediated regulation of renal sodium excretion

Transcriptional profiling of C57 and DBA strains of mice in the absence and presence of morphine

BACKGROUND: The mouse C57BL/6 (C57) and DBA/2J (DBA) inbred strains differ substantially in many aspects of their response to drugs of abuse. The development of microarray analyses represents a genome-wide method for measuring differences across strains, focusing on expression differences. In the current study, we carried out microarray analysis in C57 and DBA mice in the nucleus accumbens of drug-naïve and morphine-treated animals. RESULTS: We identified mRNAs with altered expression between the two strains. We validated the mRNA expression changes of several such mRNAs, including Gnb1, which has been observed to be regulated by several drugs of abuse. In addition, we validated alterations in the enzyme activity of one mRNA product, catechol-O-methyltransferase (Comt). Data mining of expression and behavioral data indicates that both Gnb1 and Comt expression correlate with aspects of drug response in C57/DBA recombinant inbred strains. Pathway analysis was carried out to identify pathways showing significant alterations as a result of treatment and/or due to strain differences. These analyses identified axon guidance genes, particularly the semaphorins, as showing altered expression in the presence of morphine, and plasticity genes as showing altered expression across strains. Pathway analysis of genes showing strain by treatment interaction suggest that the phosphatidylinositol signaling pathway may represent an important difference between the strains as related to morphine exposure. CONCLUSION: mRNAs with differing expression between the two strains could potentially contribute to strain-specific responses to drugs of abuse. One such mRNA is Comt and we hypothesize that altered expression of Comt may represent a potential mechanism for regulating the effect of, and response to, multiple substances of abuse. Similarly, a role for Gnb1 in responses to multiple drugs of abuse is supported by expression data from our study and from other studies. Finally, the data support a role for semaphorin signaling in morphine effects, and indicate that altered expression of genes involved in phosphatidylinositol signaling and plasticity might also affect the altered drug responses in the two strains

Catechol-O-methyltransferase (COMT) protein expression and activity after dopaminergic and noradrenergic lesions of the rat brain

Peer reviewe

Epistasis between polymorphisms in COMT, ESR1, and GCH1 influences COMT enzyme activity and pain

Abnormalities in the enzymatic activity of catechol-O-methyltransferase (COMT) contribute to chronic pain conditions, such as temporomandibular disorders (TMD). Thus, we sought to determine the effects of polymorphisms in COMT and functionally-related pain genes in the COMT pathway (estrogen receptor 1: ESR1, guanosine-5-triphosphate cyclohydrolase 1: GCH1, methylenetetrahydrofolate reductase: MTHFR) on COMT enzymatic activity, musculoskeletal pain, and pain-related intermediate phenotypes among TMD cases and healthy controls. Results demonstrate that the COMT rs4680 (val158met) polymorphism is most strongly associated with outcome measures, such that individuals with the minor A allele (met) exhibit reduced COMT activity, increased TMD risk, and increased musculoskeletal pain. Epistatic interactions were observed between the COMT rs4680 polymorphism and polymorphisms in GCH1 and ESR1. Among individuals with the COMT met allele, those with two copies of the GCH1 rs10483639 minor G allele exhibit normalized COMT activity and increased mechanical pain thresholds. Among individuals with the COMT val allele, those with two copies of the ESR1 rs3020377 minor A allele exhibit reduced COMT activity, increased bodily pain, and poorer self-reported health. These data reveal that the GCH1 minor G allele confers a protective advantage among met carriers, while the ESR1 minor A allele is disadvantageous among val carriers. Furthermore, these data suggest that the ability to predict the downstream effects of genetic variation on COMT activity is critically important to understanding the molecular basis of chronic pain conditions

InDEx – Industrial Data Excellence

InDEx, the Industrial Data Excellence program, was created to investigate what industrial data can be collected, shared, and utilized for new intelligent services in high-performing, reliable and secure ways, and how to accomplish that in practice in the Finnish manufacturing industry.InDEx produced several insights into data in an industrial environment, collecting data, sharing data in the value chain and in the factory environment, and utilizing and manipulating data with artificial intelligence. Data has an important role in the future in an industrial context, but data sources and utilization mechanisms are more diverse than in cases related to consumer data. Experiences in the InDEx cases showed that there is great potential in data utili zation.Currently, successful business cases built on data sharing are either company-internal or utilize an existing value chain. The data market has not yet matured, and third-party offerings based on public and private data sources are rare. In this program, we tried out a framework that aimed to securely and in a controlled manner share data between organizations. We also worked to improve the contractual framework needed to support new business based on shared data, and we conducted a study of applicable business models. Based on this, we searched for new data-based opportunities within the project consortium. The vision of data as a tradeable good or of sharing with external partners is still to come true, but we believe that we have taken steps in the right direction.The program started in fall 2019 and ended in April 2022. The program faced restrictions caused by COVID-19, which had an effect on the intensity of the work during 2020 and 2021, and the program was extended by one year. Because of meeting restrictions, InDEx collaboration was realized through online meetings. We learned to work and collaborate using digital tools and environments. Despite the mentioned hindrances, and thanks to Business Finland’s flexibility, the extension time made it possible for most of the planned goals to be achieved.This report gives insights in the outcomes of the companies’ work within the InDEx program. DIMECC InDEx is the first finalized program by the members of the Finnish Advanced Manufacturing Network (FAMN, www.famn.fi).</p

Ydinvoimalaitosten järjestelmien, rakenteiden ja komponenttien riskitietoinen luokittelu

Säteilyturvakeskuksen viranomaisohjeiden mukaan riskitietoa on syytä käyttää ydinvoimalaitosten komponenttien ja järjestelmien turvallisuustärkeyden määrittämisessä. Turvallisuusluokituksen tulee perustua laitteen tärkeyteen turvallisuuden suhteen. Tässä työssä on kehitetty kaksi erilaista metodia riskitiedon hyödyntämiseksi tähän tarkoitukseen. Työssä on tutkittu riskitärkeysmittojen tulkitsemista ja käyttöä komponenttien ja systeemien tärkeyden arvioimiseen. Riskitärkeysmittojen vertailtavuutta on parannettu käyttämällä samoja riskitärkeysmittoja sekä alkutapahtumien että perustapahtumien arviointiin, kun taas perinteisesti erilaisille tapahtumille on käytetty erityyppisiä mittoja jotka eivät ole vertailukelpoisia. Riskitärkeysmittojen ja turvallisuusluokituksen välistä yhteyttä on tutkittu, ja työssä esitellään kaksi uutta luokittelumenetelmää. Ensimmäinen soveltuu turvallisuuden kannalta tärkeiden komponenttien tunnistamiseen. Toinen on keino arvioida ydinvoimalan turvallisuustoimintojen tasapainoisuutta verrattuna onnettomuustapahtumien vakavuuteen ja tapahtumistaajuuteen