Inhibition of RNA Binding in SND1 Increases the Levels of miR-1-3p and Sensitizes Cancer Cells to Navitoclax

SND1 is an RNA-binding protein overexpressed in large variety of cancers. SND1 has been proposed to enhance stress tolerance in cancer cells, but the molecular mechanisms are still poorly understood. We analyzed the expression of 372 miRNAs in the colon carcinoma cell line and show that SND1 silencing increases the expression levels of several tumor suppressor miRNAs. Furthermore, SND1 knockdown showed synergetic effects with cancer drugs through MEK-ERK and Bcl-2 family-related apoptotic pathways. To explore whether the SND1-mediated RNA binding/degradation is responsible for the observed effect, we developed a screening assay to identify small molecules that inhibit the RNA-binding function of SND1. The screen identified P2X purinoreceptor antagonists as the most potent inhibitors. Validation confirmed that the best hit, suramin, inhibits the RNA binding ability of SND1. The binding characteristics and mode of suramin to SND1 were characterized biophysically and by molecular docking that identified positively charged binding cavities in Staphylococcus nuclease domains. Importantly, suramin-mediated inhibition of RNA binding increased the expression of miR-1-3p, and enhanced sensitivity of cancer cells to Bcl-2 inhibitor navitoclax treatment. Taken together, we demonstrate as proof-of-concept a mechanism and an inhibitor compound for SND1 regulation of the survival of cancer cells through tumor suppressor miRNAs

Inhibition of RNA Binding in SND1 Increases the Levels of miR-1-3p and Sensitizes Cancer Cells to Navitoclax

SND1 is an RNA-binding protein overexpressed in large variety of cancers. SND1 has been proposed to enhance stress tolerance in cancer cells, but the molecular mechanisms are still poorly understood. We analyzed the expression of 372 miRNAs in the colon carcinoma cell line and show that SND1 silencing increases the expression levels of several tumor suppressor miRNAs. Furthermore, SND1 knockdown showed synergetic effects with cancer drugs through MEK-ERK and Bcl-2 family-related apoptotic pathways. To explore whether the SND1-mediated RNA binding/degradation is responsible for the observed effect, we developed a screening assay to identify small molecules that inhibit the RNA-binding function of SND1. The screen identified P2X purinoreceptor antagonists as the most potent inhibitors. Validation confirmed that the best hit, suramin, inhibits the RNA binding ability of SND1. The binding characteristics and mode of suramin to SND1 were characterized biophysically and by molecular docking that identified positively charged binding cavities in Staphylococcus nuclease domains. Importantly, suramin-mediated inhibition of RNA binding increased the expression of miR-1-3p, and enhanced sensitivity of cancer cells to Bcl-2 inhibitor navitoclax treatment. Taken together, we demonstrate as proof-of-concept a mechanism and an inhibitor compound for SND1 regulation of the survival of cancer cells through tumor suppressor miRNAs

Software Framework for Data Fault Injection to Test Machine Learning Systems

Peer reviewe

Food waste amount, type, and climate impact in urban and suburban regions in Finnish households

Households produce about half the food waste in Europe, significantly affecting the environment and society. To measure and understand all the impact, there is a need for both primary and direct data, as well as an evaluation of methods. To respond to this need, new knowledge about households' FW and the applicability of waste composition analysis method in urban housing and areas is provided. This knowledge is applicable for planning FW studies, considering various measurement methods, the extrapolation of country-level FW values, and the introduction of decreasing interventions for households. The novelty of this study lies in its comprehensiveness: outcomes from three different city regions are analysed, and the method's robustness is evaluated. The goal of this research was to study the amount and quality of food waste in mixed waste and separately collected biowaste in Finnish households. Other goals were to estimate the unnecessary climate impact of lost food and to assess the validity of the chosen methodology. The study responds to the lack of comprehensive and recent first-hand data and reports results from three different city areas, using a relatively large number of samples that encompass 98,000 inhabitants, or about 50,000 households. The data were collected on four separate occasions: in the Helsinki area during September 2015 and October 2018, in the Turku area during June 2019, and in the Tampere area during September 2016. The results suggested that the average amount of food waste varied between 53.0 kg/cap/y and 62.1 kg/cap/y, and the amount of originally edible food waste varied between 23.0 kg/cap/y and 28.4 kg/cap/y. When extrapolating the food waste results to all study areas, the Helsinki produced about 57,000–62,000 t/y, Tampere about 16,000 t/y, and Turku about 25,000 t/y, for a total of about 100,000 t/y. The Meat and fish type group contributed most to the climate impact of originally edible FW (37–47%), while its share of food waste was much smaller, at 10–12%. The total climate impact was assessed as 0.10 Mt CO2eq/y when the climate impacts per capita annually ranged from 52.9 kg CO2eq/cap/y to 61.4 kg CO2eq/cap/y in the different regions. Due to the results' consistency, the waste composition analysis methodology can be recommended for measuring FW from both mixed and biowaste flows in urban and suburban areas. The study was conducted in cooperation with local waste management companies to increase resource efficiency and the opportunities to share facilities and to decrease study costs

Ruokahävikin mittaaminen ja hävikin vähennyskeinot ravitsemispalveluissa: CIRCWASTE Deliverable C5.1

Tässä raportissa esitellään CIRCWASTE -hankkeen tuotoksia. Projektissa selvitettiin, miten vähentää ja mitata ruokahävikkiä ravitsemispalveluissa ja erityisesti linjastoruokailuissa. Lisäksi selvitettiin, miten henkilökunnan osallistaminen vähennystoimiin ja asiakkaille suunnattu informaatio vaikuttivat syntyviin ruokahävikkimääriin. Mittaukset ja kampanjat toteutettiin kuudessa koulussa ja kahdessa henkilöstöravintolassa Varsinais-Suomessa ja Satakunnassa. Hävikkimääriä seurattiin syksyn 2017 ja kevään 2018 ajan siten, että ensin suoritettiin lähtötason mittaus ja tämän jälkeen mittausta jatkettiin vähentämistoimien ja kampanjoiden aikana vaikutusten seuraamiseksi. Mittaaminen tehtiin erityisellä hävikin kirjaamiseen tarkoitetulla online-sovelluksella ja asiakkaiden lautastähteen mittaamiseen kehitetyllä vaakalaitteistolla. Kampanjassa toteutettiin erilaisia asiakkaille suunnattuja tietoiskuja ruokahävikistä ja sen vaikutuksista. Ravitsemispalveluiden henkilökunnalle järjestettiin toistuvia hävikkipalavereja, joissa vähennyskeinoja ideoitiin ja kehitettiin. Suurimmat hävikkimäärät suhteessa valmistettuun ruokaan syntyivät tarjoiluhävikistä. Syitä tarkasteltaessa tuloksista voidaan löytää seuraavia tekijöitä: ruokaa valmistetaan tai tilataan liikaa, asiakasmäärien arviointi on vaikeaa, tietyt ruokalajit tai dieettiruoat voivat lisätä hävikkiä ja esim. palvelusopimus asettaa tiettyjä reunaehtoja ruokailujen järjestämiseen. Hävikkiä ei saatu mittausjakson aikana vähentymään. Haastatteluiden perusteella tämä johtui juuri mittausjaksolle osuneista lukuisista henkilövaihdoksista ja muista isoista muutoksista toimipisteiden perustoiminnoissa. Kampanjasta huolimatta myöskään asiakkaiden lautastähteinä syntyvää ruokahävikkiä ei saatu vähentymään kuin yhdessä toimipisteessä. Asiakaskyselyn perusteella kuitenkin sekä oppilaat että henkilöstöruokailijat suhtautuivat myönteisesti hävikin mittaamiseen ja vähentämiseen. Oppilaat kertoivat, että kampanjan vaikutuksesta he ovat heittäneet vähemmän ruokaa pois. Tätä ei kuitenkaan siis mittauksella voitu todeta. Projektissa kerätyn tiedon perusteella henkilökunta suhtautui myönteisesti hävikin vähentämiseen ja mittaukseen. Mittaus ei vienyt liikaa aikaa ja sujui hyvin alkuopastuksen jälkeen. Tulosten perusteella laadittiin parhaiden käytäntöjen listaus (luku 4.1), johon on koottu toimivia keinoja hävikin vähentämiseen. Tärkeimpinä keinoina ovat järjestelmällinen perustoiminta, johtamisen ja suunnittelun kehittäminen sekä ruokahävikin mittaaminen, jolloin eri vähennyskeinojen toimivuutta voidaan seurata. Jatkossa hävikin vähentämistä ja mittaamista pitää edelleen kehittää: Tulosten pohjalta mittaaminen tulisi ottaa osaksi koulutusta ja työhön perehdytystä sekä tuoda tulokset näkyväksi myös asiakkaille. Konkreettisia jatkotutkimusehdotuksia ovat myös tässä projektissa tärkeiksi nousseet palvelusopimusten merkitys hävikin vähentämisessä, mittaamisen hyödyntäminen ruokalistasuunnittelussa ja viestintä asiakkaiden kanssa siten, että hekin voivat omalta osaltaan vähentää hävikkiä. Asiakkaiden kanssa kommunikoinnilla voidaan pyrkiä esimerkiksi siihen, että he hyväksyvät näkyvien hävikkiä vähentävien keinojen käyttämisen (kuten ruokalistan mukaisen ruuan loppumiseen tarjoiluhävikin minimoimiseksi).201

New digital learning materials for teaching in geosciences

Non peer reviewe

Activin Receptor Ligand Blocking and Cancer Have Distinct Effects on Protein and Redox Homeostasis in Skeletal Muscle and Liver

Muscle wasting in cancer cachexia can be alleviated by blocking activin receptor type 2 (ACVR2) ligands through changes in protein synthesis/degradation. These changes in cellular and protein metabolism may alter protein homeostasis. First, we elucidated the acute (1-2 days) and 2-week effects of blocking ACVR2 ligands by soluble activin receptor 2B (sACVR2B-Fc) on unfolded protein response (UPR), heat shock proteins (HSPs) and redox balance in a healthy mouse skeletal muscle. Second, we examined UPR, autophagy and redox balance with or without sACVR2B-Fc administration in muscle and liver of C26 tumor-bearing mice. The indicators of UPR and HSPs were not altered 1-2 days after a single sACVR2B-Fc administration in healthy muscles, but protein carbonyls increased (p <0.05). Two weeks of sACVR2B-Fc administration increased muscle size, which was accompanied by increased UPR markers: GRP78 <0.05), phosphorylated elF2 alpha <0.01) and HSP47 (p <0.01). Additionally, protein carbonyls and reduced form of glutathione increased (GSH) (p <0.05). On the other hand, C26 cancer cachexia manifested decreased UPR markers (p-elF2 alpha, HSP47, p-JNK; p <0.05) and antioxidant GSH (p <0.001) in muscle, whereas the ratio of oxidized to reduced glutathione increased (GSSG/GSH; p <0.001). Administration of sACVR2B-Fc prevented the decline in GSH and increased some of the UPR indicators in tumor-bearing mice. Additionally, autophagy markers LC3II/I (p <0.05), Beclin-1 (p <0.01), and P62 (p <0.05) increased in the skeletal muscle of tumor-bearing mice. Finally, indicators of UPR, PERK, p-elF2 alpha and GRP78, increased (p <0.05), whereas ATF4 was strongly decreased (p <0.01) in the liver of tumor-bearing mice while sACVR2B-Fc had no effect. Muscle GSH and many of the altered UPR indicators correlated with tumor mass, fat mass and body mass loss. In conclusion, experimental cancer cachexia is accompanied by distinct and tissue-specific changes in proteostasis. Muscle hypertrophy induced by blocking ACVR2B ligands may be accompanied by the induction of UPR and increased protein carbonyls but blocking ACVR2B ligands may upregulate antioxidant protection.Peer reviewe

A germline exome analysis reveals harmful POT1 variants in multiple myeloma patients and families

Peer reviewe

Prognostic significance of esterase gene expression in multiple myeloma

Background Esterase enzymes differ in substrate specificity and biological function and may display dysregulated expression in cancer. This study evaluated the biological significance of esterase expression in multiple myeloma (MM). Methods For gene expression profiling and evaluation of genomic variants in the Institute for Molecular Medicine Finland (FIMM) cohort, bone marrow aspirates were obtained from patients with newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM). CD138+ plasma cells were enriched and used for RNA sequencing and analysis, and to evaluate genomic variation. The Multiple Myeloma Research Foundation (MMRF) Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass) dataset was used for validation of the findings from FIMM. Results MM patients (NDMM, n = 56; RRMM, n = 78) provided 171 bone marrow aspirates (NDMM, n = 56; RRMM, n = 115). Specific esterases exhibited relatively high or low expression in MM, and expression of specific esterases (UCHL5, SIAE, ESD, PAFAH1B3, PNPLA4 and PON1) was significantly altered on progression from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, SIAE and USP4, and low expression of PCED1B, were identified as poor prognostic markers (P <0.05). The MMRF CoMMpass dataset provided validation that higher expression of PAFAH1B3 and SIAE, and lower expression of PCED1B, were associated with poor prognosis. Conclusions Esterase gene expression levels change as patients progress from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, USP4 and SIAE, and low expression of PCED1B, are poor prognostic markers in MM, suggesting a role for these esterases in myeloma biology.Peer reviewe

Lethal effects of waterlogging on Scots pine appear with delay

Poster