Transcriptional and functional effects of lithium in bipolar disorder iPSC-derived cortical spheroids

Lithium (Li) is recommended for long-term treatment of bipolar disorder (BD). However, its mechanism of action is still poorly understood. Induced pluripotent stem cell (iPSC)-derived brain organoids have emerged as a powerful tool for modeling BD-related disease mechanisms. We studied the effects of 1 mM Li treatment for 1 month in iPSC-derived human cortical spheroids (hCS) from 10 healthy controls (CTRL) and 11 BD patients (6 Li-responders, Li-R, and 5 Li non-treated, Li-N). At day 180 of differentiation, BD hCS showed smaller size, reduced proportion of neurons, decreased neuronal excitability and reduced neural network activity compared to CTRL hCS. Li rescued excitability of BD hCS neurons by exerting an opposite effect in the two diagnostic groups, increasing excitability in BD hCS and decreasing it in CTRL hCS. We identified 132 Li-associated differentially expressed genes (DEGs), which were overrepresented in sodium ion homeostasis and kidney-related pathways. Moreover, Li regulated secretion of pro-inflammatory cytokines and increased mitochondrial reserve capacity in BD hCS. Through long-term Li treatment of a human 3D brain model, this study partly elucidates the functional and transcriptional mechanisms underlying the clinical effects of Li, such as rescue of neuronal excitability and neuroprotection. Our results also underscore the substantial influence of treatment duration in Li studies. Lastly, this study illustrates the potential of patient iPSC-derived 3D brain models for precision medicine in psychiatry.publishedVersio

Shared genetic architecture between irritable bowel syndrome and psychiatric disorders reveals molecular pathways of the gut-brain axis

Background: Irritable bowel syndrome (IBS) often co-occurs with psychiatric and gastrointestinal disorders. A recent genome-wide association study (GWAS) identified several genetic risk variants for IBS. However, most of the heritability remains unidentified, and the genetic overlap with psychiatric and somatic disorders is not quantified beyond genome-wide genetic correlations. Here, we characterize the genetic architecture of IBS, further, investigate its genetic overlap with psychiatric and gastrointestinal phenotypes, and identify novel genomic risk loci. Methods: Using GWAS summary statistics of IBS (53,400 cases and 433,201 controls), and psychiatric and gastrointestinal phenotypes, we performed bivariate casual mixture model analysis to characterize the genetic architecture and genetic overlap between these phenotypes. We leveraged identified genetic overlap to boost the discovery of genomic loci associated with IBS, and to identify specific shared loci associated with both IBS and psychiatric and gastrointestinal phenotypes, using the conditional/conjunctional false discovery rate (condFDR/conjFDR) framework. We used functional mapping and gene annotation (FUMA) for functional analyses. Results: IBS was highly polygenic with 12k trait-influencing variants. We found extensive polygenic overlap between IBS and psychiatric disorders and to a lesser extent with gastrointestinal diseases. We identified 132 independent IBS-associated loci (condFDR < 0.05) by conditioning on psychiatric disorders (n = 127) and gastrointestinal diseases (n = 24). Using conjFDR, 70 unique loci were shared between IBS and psychiatric disorders. Functional analyses of shared loci revealed enrichment for biological pathways of the nervous and immune systems. Genetic correlations and shared loci between psychiatric disorders and IBS subtypes were different. Conclusions: We found extensive polygenic overlap of IBS and psychiatric and gastrointestinal phenotypes beyond what was revealed with genetic correlations. Leveraging the overlap, we discovered genetic loci associated with IBS which implicate a wide range of biological pathways beyond the gut-brain axis. Genetic differences may underlie the clinical subtype of IBS. These results increase our understanding of the pathophysiology of IBS which may form the basis for the development of individualized interventions.publishedVersio

Polygenic overlap with body-mass index improves prediction of treatment-resistant schizophrenia

Treatment resistant schizophrenia (TRS) is characterized by repeated treatment failure with antipsychotics. A recent genome-wide association study (GWAS) of TRS showed a polygenic architecture, but no significant loci were identified. Clozapine is shown to be the superior drug in terms of clinical effect in TRS; at the same time it has a serious side effect profile, including weight gain. Here, we sought to increase power for genetic discovery and improve polygenic prediction of TRS, by leveraging genetic overlap with Body Mass Index (BMI). We analysed GWAS summary statistics for TRS and BMI applying the conditional false discovery rate (cFDR) framework. We observed cross-trait polygenic enrichment for TRS conditioned on associations with BMI. Leveraging this cross-trait enrichment, we identified 2 novel loci for TRS at cFDR <0.01, suggesting a role of MAP2K1 and ZDBF2. Further, polygenic prediction based on the cFDR analysis explained more variance in TRS when compared to the standard TRS GWAS. These findings highlight putative molecular pathways which may distinguish TRS patients from treatment responsive patients. Moreover, these findings confirm that shared genetic mechanisms influence both TRS and BMI and provide new insights into the biological underpinnings of metabolic dysfunction and antipsychotic treatment.publishedVersio

Rester av plantevernmidler i frukt og grønnsaker

Mattilsynet har overvåket nivået av plantevernmiddelrester i mat på det norske markedet siden 1977. De siste årene er det blitt analysert rundt 1500 stikkprøver fra norskproduserte og importerte varepartier, hvorav 40 prosent er prøver av norske varer. Antall stoffer det søkes etter har økt betydelig de siste årene, og i 2010 vil hver prøve av frukt og grønnsaker bli analysert for 265 forskjellige stoffer. Bioforsk Plantehelse er ansvarlig for analysene.publishedVersio

Plantevernmidler i vann - miljørisiko

Det er et mål at kjemiske plantevernmidler i størst mulig grad skal forsvinne fra det biologiske systemet når de har hatt sin tilsiktede virkning på skadegjørere. De skal dermed ikke finnes igjen i mengder av betydning i jord, grunnvann eller overflatevann. Overvåking av spesielt utsatte vannressurser i Norge gjennom Program for jord- og vannovervåking i landbruket (JOVA-programmet) viser imidlertid mange funn av plantevernmiddelrester. Miljørisikoen knyttet til disse funnene vurderes ut fra beregnede miljøfarlighetsverdier (MF-verdier) for de ulike plante-vernmidlene

Plantevernmidler i vann – Miljørisiko

Det er et mål at kjemiske plantevernmidler i størst mulig grad skal forsvinne fra det biologiske systemet når de har hatt sin tilsiktede virkning på skadegjørere. De skal dermed ikke finnes igjen i mengder av betydning i jord, grunnvann eller overflatevann. Overvåking av spesielt utsatte vannressurser i Norge gjennom Program for jord- og vannovervåking i landbruket (JOVA-programmet) viser imidlertid mange funn av plantevernmiddelrester. Miljørisikoen knyttet til disse funnene vurderes ut fra beregnede miljøfarlighetsverdier (MF-verdier) for de ulike plantevernmidlene.publishedVersio

Rester av plantevernmidler i maten vi spiser

Plantevernmidler benyttes for å forhindre skade på planter forårsaket av sopper, skadedyr og ugras. Det er streng kontroll med salg og bruk av plantevernmidler. Kontrollen skal forhindre at plantevernmidler gjør skade på mennesker, dyreliv og miljø. Det har vært en egen godkjenningsordning for import og bruk av slike midler siden 1954. I dag forvaltes denne ordningen av Mattilsynet. I tillegg utfører Mattilsynet i samarbeid med Bioforsk en årlig overvåking av rester av plantevernmidler i mat. Overvåkingen for rester av plantevernmidler i mat startet i 1977.publishedVersio

Fusarium and mycotoxin content of harvested grain was not related to tillage intensity in Norwegian spring wheat fields

To mitigate the risk of erosion and nutrient runoff, reduced tillage has become more prevalent in Norway. Within within recent decades, there have been some years with relatively high occurrence of Fusarium head blight and mycotoxins in Norwegian cereal grain. This is thought to have been caused by an increased inoculum potential (IP) of Fusarium spp. due to larger amount of crop residues remaining on the soil surface, in combination with weather conditions promoting fungal growth and infection of cereal plants. The objective of this work was to elucidate the influence of different tillage practices on the IP of Fusarium spp. and the subsequent Fusarium-infection and mycotoxin contamination of spring wheat grain at harvest. Tillage trials were conducted at two locations in southeast Norway (Solør and Toten) over three years, 2010-2012. Residues of wheat from the previous year were collected in spring. Fusarium avenaceum and Fusarium graminearum were the most common Fusarium species recorded on wheat straw residues. IP was calculated as the percentage of the residues infested with Fusarium spp. multiplied by the proportion of the soil surface covered with residues. The IP of Fusarium spp. was lower in ploughed plots compared to those tilled with harrowing only. Ploughing in spring resulted in a similarly low IP as autumn ploughing. In contrast, harrowing in autumn generally reduced IP more than did spring harrowing. The mycotoxin levels in the harvested wheat were generally low, except for deoxynivalenol at high levels in Solør 2011. Despite a lower IP of ploughed versus harrowed plots, this was not reflected in the content of Fusarium and mycotoxins in harvested grain. The Fusarium species that dominated in the residues examined in this study were the same as those detected in the harvested grain, supporting the finding that residues are an important source of inoculum.publishedVersio

Chemical and microbiological hazards associated with recycling of anaerobic digested residue intended for agricultural use

In the present study, three full-scale biogas plants (BGP) were investigated for the concentration of heavy metals, organic pollutants, pesticides and the pathogenic bacteria Bacillus cereus and Escherichia coli in the anaerobically digested residues (ADR). The BGPs mainly utilize source-separated organic wastes and industrial food waste as energy sources and separate the ADR into an ADR-liquid and an ADR-solid fraction by centrifugation at the BGP. According to the Norwegian standard for organic fertilizers, the ADR were classified as quality 1 mainly because of high zinc (132–422 mg kg−1 DM) and copper (23–93 mg kg−1 DM) concentrations, but also because of high cadmium (0.21–0.60 mg kg−1 DM) concentrations in the liquid-ADR. In the screening of organic pollutants, only DEHP (9.7–62.1 mg kg−1) and ∑ PAH 16 (0.2–1.98 mg kg−1 DM) were detected in high concentrations according to international regulations. Of the 250 pesticides analyzed, 11 were detected, but only imazalil (<0.30–5.77 mg kg−1 DM) and thiabendazol (<0.14–0.73 mg kg−1 DM) were frequently detected in the ADR-fiber. Concentrations of imazalil and thiabendazol were highest during the winter months, due to a high consumption of citrus fruits in Norway in this period. Ten percent of the ADR-liquid samples contained cereulide-producing B. cereus, whereas no verotoxigenic E. coli was detected. The authors conclude that the risk of chemical and bacterial contamination of the food chain or the environment from agricultural use of ADR seems low