Biology subjects

Schaefer, B.

Publications and source records attributed to Schaefer, B..

4 recordsLinked to original sources

bioRxiv2024

Converging effects of cannabis and psychosis on the dopamine system: A longitudinal neuromelanin-sensitive MRI study in cannabis use disorder and first episode schizophrenia.

ImportanceDespite evidence that individuals who use cannabis early in life are at elevated risk of psychosis and that the neurotransmitter dopamine has a role in both conditions, the mechanism linking the two conditions remains unclear. ObjectiveTo use neuromelanin-sensitive MRI (neuromelanin-MRI), a practical, proxy measure of dopamine function, to assess whether a common alteration in the dopamine system may be implicated in cannabis use and psychosis and whether this alteration can be observed in cannabis users whether or not they have a diagnosis of first-episode schizophrenia. Design, Setting, and ParticipantsThis longitudinal observational study recruited participants from 2019 to 2023 from an early intervention service for psychosis in London, Ontario, Canada. The sample consisted of 25 participants with cannabis use disorder (CUD) and 36 participants without CUD (nCUD), of which 28 had first-episode schizophrenia (FES). One-year follow-up was completed for 12 CUD and 25 nCUD participants. Main Outcomes and MeasuresNeuromelanin-MRI contrast within the substantia nigra (SN) and within a subregion previously linked to psychosis severity (a priori psychosis region of interest) and diagnoses of schizophrenia-spectrum disorder and cannabis use disorder derived from the Structured Clinical Interview for DSM-5. Linear mixed effects analyses were performed relating neuromelanin-MRI contrast to clinical measures. ResultsWe found that CUD was associated with elevated neuromelanin-MRI signal in a cluster of ventral SN voxels (387 of 2060 SN voxels, pcorrected=0.027, permutation test). Furthermore, CUD was associated with elevated neuromelanin-MRI signal in an SN subregion previously documented to have elevated signal in relation to untreated psychotic symptoms (t92 =2.12, p=0.037). In contrast, FES was not associated with a significant alteration in neuromelanin-MRI signal (241 SN voxels had elevated signal, pcorrected=0.094). Conclusions and RelevanceThese findings suggest that elevated dopamine function in a critical SN subregion may contribute to the risk of psychosis in people with CUD. Thus, cannabis affects the long-suspected final common pathway for the clinical expression of psychotic symptoms. Imaging the dopamine system with neuromelanin-MRI may index long-term dopamine turnover. Key PointsO_ST_ABSQuestionC_ST_ABSIs the same midbrain dopamine pathway impacted by cannabis as in psychosis? FindingsCannabis use disorder participants had elevated neuromelanin-MRI signal in a cluster of ventral substantia nigra voxels and in a subregion previously documented to have elevated signal in relation to untreated psychotic symptoms. MeaningIncreased dopamine functioning in the ventral substantia nigra may contribute to the risk of psychosis in people with cannabis use disorders.

neuroscience↗

bioRxiv2024

BCL-2 and BOK regulate apoptosis by interaction of their C-terminal transmembrane domains

The Bcl-2 family controls apoptosis by direct interactions of pro- and anti-apoptotic proteins. The principle mechanism is binding of the BH3 domain of pro-apoptotic proteins to the hydrophobic groove of anti-apoptotic siblings, which is therapeutically exploited by approved BH3-mimetic anti-cancer drugs. Evidence suggests that also the transmembrane domain (TMD) of Bcl-2 proteins affects Bcl-2 interactions. We developed a highly-specific split luciferase assay, enabling the analysis of TMD interactions of pore-forming apoptosis effectors BAX, BAK, and BOK with anti-apoptotic Bcl-2 proteins in living cells. We confirm homotypic interaction of the BAX-TMD, but also newly identify interaction of the TMD of anti-apoptotic BCL-2 with the TMD of BOK, a so far very peculiar pro-apoptotic Bcl-2 protein. Interaction of BOK-TMD with BCL-2-TMD localizes at the endoplasmic reticulum (ER). Molecular dynamics simulations in an ER membrane model confirm dynamic BOK-TMD and BCL-2-TMD homo- and heterodimers and stable heterotetramers. Inhibition of BOK-induced apoptosis by BCL-2 depends specifically on their TMDs. Thus, TMDs of Bcl-2 proteins are a relevant interaction interface for apoptosis regulation and provide a novel potential drug target.

molecular biology↗

bioRxiv2021

Interleukin-11 plays a key role in human and mouse alcohol-related liver disease

BackgroundAlcoholic hepatitis (AH) reflects acute exacerbation of alcoholic liver disease (ALD) and is a growing healthcare burden worldwide with limited treatment options. Interleukin-11 (IL-11) is a pro-fibrotic, pro-inflammatory cytokine with increasingly recognized toxicities in parenchymal and epithelial cells. AimThe aim of this study was to explore the prognostic value of IL-11 serum levels in patients suffering from AH and cirrhosis of various etiology and to understand the role of IL-11 in experimental ALD. MethodsIL-11 serum concentration and tissue expression was determined in a cohort comprising 50 patients with AH, 110 patients with cirrhosis and 19 healthy volunteers. Findings were replicated in an independent patient cohort including 186 patients. Ethanol-fed wildtype mice were treated with a neutralizing murine IL-11 receptor-antibody (anit-IL11RA) and thereafter examined for severity signs and markers of ALD. ResultsHuman IL-11 serum concentration and liver tissue expression increased with severity of liver disease and were most pronounced in AH. In a multivariate Cox-regression, a serum level above 6.4 picograms/milliliter was a MELD independent risk factor for transplant-free liver disease survival in patients with compensated and decompensated cirrhosis. Findings were confirmed in an independent cohort. In mice, severity of alcohol-induced liver inflammation was positively correlated to enhanced hepatic IL-11 expression. Pretreatment with a neutralizing anti-IL11RA inhibited hepatic inflammation and mice were protected from ethanol-induced liver injury. In comparison to IgG-control, ethanol-fed mice treated with anti-IL11RA showed decreased steatosis, hepatic neutrophil infiltration, and expression of pro-inflammatory cytokines. ConclusionIL-11 plays a crucial role in the pathogenesis of ALD and could serve as an independent prognostic factor for transplant-free survival. Blocking IL-11 signaling might be a therapeutic option in human ALD, particularly AH.

immunology↗

bioRxiv2019

Miswired enhancer logic drives translocation positive rhabdomyosarcoma

Core regularity transcription factors (CR TFs) define cell identity and lineage through an exquisitely precise and logical order during embryogenesis and development. These CR TFs regulate one another in three-dimensional space via distal enhancers that serve as logic gates embedded in their TF recognition sequences. Aberrant chromatin organization resulting in miswired circuitry of enhancer logic is a newly recognized feature in many cancers. Here, we report that PAX3-FOXO1 expression is driven by a translocated FOXO1 distal super enhancer (SE). Using 4C-seq, a technique detecting all genomic regions that interact with the translocated FOXO1 SE, we demonstrate its physical interaction with the PAX3 promotor only in the presence of the oncogenic translocation. Furthermore, RNA-seq and ChIP-seq in tumors bearing rare PAX translocations implicate enhancer miswiring is a pervasive feature across all FP-RMS tumors. HiChIP of enhancer mark H3K27ac showed extended connectivity between the distal FOXO1 SE and additional intra-domain enhancers and the PAX3 promoter. We show by CRISPR-paired-ChIP-Rx that PAX3-FOXO1 transcription is diminished when this network of enhancers is selectively ablated. Therefore, our data reveal a mechanism of a translocated hijacked enhancer which disrupts the normal CR TF logic during skeletal muscle development (PAX3 to MYOD to MYOG), replacing it with an infinite loop logic that locks rhabdomyosarcoma cells in an undifferentiated proliferating stage.

cancer biology↗