NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) : characterisation of a novel cerebropulmonary disease

A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. In the affected children, neuropathology revealed increased angiomatosis-like leptomeningeal, cortical and superficial white matter vascularisation and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver. A whole-exome sequencing of the two unrelated families with the affected children revealed the transmission of two heterozygous variants in the NHL repeat-containing protein 2 (NHLRC2); an amino acid substitution p.Asp148Tyr and a frameshift 2-bp deletion p.Arg201GlyfsTer6. NHLRC2 is highly conserved and expressed in multiple organs and its function is unknown. It contains a thioredoxin-like domain; however, an insulin turbidity assay on human recombinant NHLRC2 showed no thioredoxin activity. In patient-derived fibroblasts, NHLRC2 levels were low, and only p.Asp148Tyr was expressed. Therefore, the allele with the frameshift deletion is likely non-functional. Development of the Nhlrc2 null mouse strain stalled before the morula stage. Morpholino knockdown of nhlrc2 in zebrafish embryos affected the integrity of cells in the midbrain region. This is the first description of a fatal, early-onset disease; we have named it FINCA disease based on the combination of pathological features that include fibrosis, neurodegeneration, and cerebral angiomatosis.Peer reviewe

Machine learning and the identification of Smart Specialisation thematic networks in Arctic Scandinavia

Abstract The European Union (EU) has recognized that universities and research institutes play a critical role in regional Smart Specialisation processes. Our research aims to identify thematic cross-border research domains across space and disciplines in Arctic Scandinavia. We identify potential domains using an unsupervised machine-learning technique (topic modelling). We uncover latent topics based on similarities in the vocabulary of research papers. The proposed methodology can be utilized to identify common research domains across regions and disciplines in almost real time, thereby acting as a decision support system to facilitate cooperation among knowledge producers

APLIKASI FOODCOURTMENGGUNAKAN MICROSOFT VISUAL STUDIO2008

Advances in computer technology requires computerization in all fields including ordering food and beverages at a food court,theauthors want to try by means of computerizedso that the application is expectedto assist in theprocessof serving food and drinks menu a restaurant which is located ina food court, and assist the process and generate a good dealof information quickly and accurately. Results obtained inscientific writing is to obtain the information presented in the form of food and beverage menu along with a description of the price of each menu. This foodcourt applications created using Microsoft VisualStudio2008 where applications can provide convenience to the user inthis case is the consumer.

A novel MTTT mutation m.15933G > A revealed in analysis of mitochondrial DNA in patients with suspected mitochondrial disease

Abstract Background: Mitochondrial diseases present with variable multi-organ symptoms. Common disease-causing mutations in mitochondrial DNA (mtDNA) are regularly screened in diagnostic work-up, but novel mutations may remain unnoticed. Methods: Patients (N = 66) with a clinical suspicion of mitochondrial disease were screened for their mtDNA coding region using conformation sensitive gel electrophoresis and sequencing. Long-PCR was used to detect deletions followed by POLG1 sequencing in patients with multiple deletions. Results: We discovered three novel mtDNA variants that included m.8743G > C, m.11322A > G and m.15933G > A. The novel MTTT variant m.15933G > A is suggested to be pathogenic. Analysis revealed also multiple mtDNA deletions in two patients and five nonsynonymous variants that were putatively pathogenic according to in-silico prediction algorithms. In addition, a rare haplogroup H associated m.7585_7586insT variant was discovered. Conclusion: Among patients with a suspected mitochondrial disease, a novel MTTT variant m.15933G > A was discovered and is suggested to be pathogenic. In addition, several putatively pathogenic nonsynonymous variants and rare variants were found. These findings highlight the importance of coding region mtDNA screening among patients with clinical features suggesting a mitochondrial disease, but who lack the common mitochondrial disease mutations

Diabeteksen kansallisen ehkäisyhankkeen pitkäaikaiset vaikutukset ja merkitys

Tiivistelmä Tyypin 2 diabeteksen ilmaantuvuus perustuen erityiskorvattavien lääkkeiden käyttöön on laskenut Suomessa koko 2010-luvun, mutta D2D-alueen sairaanhoitopiirien väliset erot ovat säilyneet. Kolmasosa D2D-hankkeessa vuosina 2003–2007 tunnistetuista suuren sairastumisriskin henkilöistä osallistui tarjottuun hoito- ja seurantaohjelmaan. Perusterveydenhuollossa ja myös työterveyshuollossa on herätty torjumaan diabetesta. Väestön diabetestietoisuus on lisääntynyt koko maassa DEHKO-ohjelman, D2D-hankkeen ja FINDRISC-diabeteksen riskitestin laajan käytön myötä. Tuloksellinen tyypin 2 diabeteksen ehkäisy edellyttää sekä korkean riskin että väestötason strategiaan perustuvia toimia ja monialaista yhteistyötä terveyttä edistävien elintapojen edistämiseksi ja omaksumiseksi

A novel variant in SMG9 causes intellectual disability, confirming a role for nonsense-mediated decay components in neurocognitive development

Abstract Biallelic loss-of-function variants in the SMG9 gene, encoding a regulatory subunit of the mRNA nonsense-mediated decay (NMD) machinery, are reported to cause heart and brain malformation syndrome. Here we report five patients from three unrelated families with intellectual disability (ID) and a novel pathogenic SMG9 c.551 T > C p.(Val184Ala) homozygous missense variant, identified using exome sequencing. Sanger sequencing confirmed recessive segregation in each family. SMG9 c.551T > C p.(Val184Ala) is most likely an autozygous variant identical by descent. Characteristic clinical findings in patients were mild to moderate ID, intention tremor, pyramidal signs, dyspraxia, and ocular manifestations. We used RNA sequencing of patients and age- and sex-matched healthy controls to assess the effect of the variant. RNA sequencing revealed that the SMG9 c.551T > C variant did not affect the splicing or expression level of SMG9 gene products, and allele-specific expression analysis did not provide evidence that the nonsense mRNA-induced NMD was affected. Differential gene expression analysis identified prevalent upregulation of genes in patients, including the genes SMOX, OSBP2, GPX3, and ZNF155. These findings suggest that normal SMG9 function may be involved in transcriptional regulation without affecting nonsense mRNA-induced NMD. In conclusion, we demonstrate that the SMG9 c.551T > C missense variant causes a neurodevelopmental disorder and impacts gene expression. NMD components have roles beyond aberrant mRNA degradation that are crucial for neurocognitive development