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Understanding the underlying mechanisms that link psychopathology and physical comorbidities in schizophrenia is crucial since decreased physical fitness and overweight pose major risk factors for cardio-vascular diseases and decrease the patients’ life expectancies. We hypothesize that altered reward anticipation plays an important role in this. We implemented the Monetary Incentive Delay task in a MR scanner and a fitness test battery to compare schizophrenia patients (SZ, n = 43) with sex- and age-matched healthy controls (HC, n = 36) as to reward processing and their physical fitness. We found differences in reward anticipation between SZs and HCs, whereby increased activity in HCs positively correlated with overall physical condition and negatively correlated with psychopathology. On the other handy, SZs revealed stronger activity in the posterior cingulate cortex and in cerebellar regions during reward anticipation, which could be linked to decreased overall physical fitness. These findings demonstrate that a dysregulated reward system is not only responsible for the symptomatology of schizophrenia, but might also be involved in physical comorbidities which could pave the way for future lifestyle therapy interventions.
RBFOX1 is a highly pleiotropic gene that contributes to several psychiatric and neurodevelopmental disorders. Both rare and common variants in RBFOX1 have been associated with several psychiatric conditions, but the mechanisms underlying the pleiotropic effects of RBFOX1 are not yet understood. Here we found that, in zebrafish, rbfox1 is expressed in spinal cord, mid- and hindbrain during developmental stages. In adults, expression is restricted to specific areas of the brain, including telencephalic and diencephalic regions with an important role in receiving and processing sensory information and in directing behaviour. To investigate the effect of rbfox1 deficiency on behaviour, we used rbfox1sa15940, a rbfox1 loss-of-function line. We found that rbfox1sa15940 mutants present hyperactivity, thigmotaxis, decreased freezing behaviour and altered social behaviour. We repeated these behavioural tests in a second rbfox1 loss-of-function line with a different genetic background, rbfox1del19, and found that rbfox1 deficiency affects behaviour similarly in this line, although there were some differences. rbfox1del19 mutants present similar thigmotaxis, but stronger alterations in social behaviour and lower levels of hyperactivity than rbfox1sa15940 fish. Taken together, these results suggest that rbfox1 deficiency leads to multiple behavioural changes in zebrafish that might be modulated by environmental, epigenetic and genetic background effects, and that resemble phenotypic alterations present in Rbfox1-deficient mice and in patients with different psychiatric conditions. Our study thus highlights the evolutionary conservation of rbfox1 function in behaviour and paves the way to further investigate the mechanisms underlying rbfox1 pleiotropy on the onset of neurodevelopmental and psychiatric disorders.
RBFOX1 is a highly pleiotropic gene that contributes to several psychiatric and neurodevelopmental disorders. Both rare and common variants in RBFOX1 have been associated with several psychiatric conditions, but the mechanisms underlying the pleiotropic effects of RBFOX1 are not yet understood. Here we found that, in zebrafish, rbfox1 is expressed in spinal cord, mid- and hindbrain during developmental stages. In adults, expression is restricted to specific areas of the brain, including telencephalic and diencephalic regions with an important role in receiving and processing sensory information and in directing behaviour. To investigate the effect of rbfox1 deficiency on behaviour, we used rbfox1sa15940, a rbfox1 loss-of-function line. We found that rbfox1sa15940 mutants present hyperactivity, thigmotaxis, decreased freezing behaviour and altered social behaviour. We repeated these behavioural tests in a second rbfox1 loss-of-function line with a different genetic background, rbfox1del19, and found that rbfox1 deficiency affects behaviour similarly in this line, although there were some differences. rbfox1del19 mutants present similar thigmotaxis, but stronger alterations in social behaviour and lower levels of hyperactivity than rbfox1sa15940 fish. Taken together, these results suggest that rbfox1 deficiency leads to multiple behavioural changes in zebrafish that might be modulated by environmental, epigenetic and genetic background effects, and that resemble phenotypic alterations present in Rbfox1-deficient mice and in patients with different psychiatric conditions. Our study thus highlights the evolutionary conservation of rbfox1 function in behaviour and paves the way to further investigate the mechanisms underlying rbfox1 pleiotropy on the onset of neurodevelopmental and psychiatric disorders.
Myocardial injury as induced by myocardial infarction results in tissue ischemia, which critically incepts cardiomyocyte death. Endothelial cells play a crucial role in restoring oxygen and nutrient supply to the heart. Latest advances in single-cell multi-omics, together with genetic lineage tracing, reveal a transcriptional and phenotypical adaptation to the injured microenvironment, which includes alterations in metabolic, mesenchymal, hematopoietic and pro-inflammatory signatures. The extent of transition in mesenchymal or hematopoietic cell lineages is still debated, but it is clear that several of the adaptive phenotypical changes are transient and endothelial cells revert back to a naïve cell state after resolution of injury responses. This resilience of endothelial cells to acute stress responses is important for preventing chronic dysfunction. Here, we summarize how endothelial cells adjust to injury and how this dynamic response contributes to repair and regeneration. We will highlight intrinsic and microenvironmental factors that contribute to endothelial cell resilience and may be targetable to maintain a functionally active, healthy microcirculation.
Besides transcription, RNA decay accounts for a large proportion of regulated gene expression and is paramount for cellular functions. Classical RNA surveillance pathways, like nonsense-mediated decay (NMD), are also implicated in the turnover of non-mutant transcripts. Whereas numerous protein factors have been assigned to distinct RNA decay pathways, the contribution of long non-coding RNAs (lncRNAs) to RNA turnover remains unknown. Here we identify the lncRNA CALA as a potent regulator of RNA turnover in endothelial cells. We demonstrate that CALA forms cytoplasmic ribonucleoprotein complexes with G3BP1 and regulates endothelial cell functions. A detailed characterization of these G3BP1-positive complexes by mass spectrometry identifies UPF1 and numerous other NMD factors having cytoplasmic G3BP1-association that is CALA-dependent. Importantly, CALA silencing impairs degradation of NMD target transcripts, establishing CALA as a non-coding regulator of RNA steady-state levels in the endothelium.
Acinetobacter baumannii can thrive on a broad range of substrates such as sugars, alcohols, lipids, amino acids and aromatic compounds. The latter three are abundant in the human host and are potential candidates as carbon sources for the metabolic adaptation of A. baumannii to the human host. In this study we determined the biodegradative activities of A. baumannii AYE with monocyclic aromatic compounds. Deletion of genes encoding the key enzymes of the ß-ketoadipate pathway, the protocatechuate-3,4-dioxygenase (ΔpcaHG) and the catechol-1,2-dioxygenase (ΔcatA), led to a complete loss of growth on benzoate and p-hydroxybenzoate, suggesting that these substrates are metabolized via the two distinct branches (pca and cat) of this pathway. Furthermore, we investigated the potential role of these gene products in host adaptation by analyzing the capability of the mutants to resist complement-mediated killing. These studies revealed that the mutants exhibit a decreased complement resistance, but a dramatic increase in survival in normal human serum in the presence of p-hydroxybenzoate or protocatechuate. These results indicate that the ß-ketoadipate pathway plays a role in adaptation of A. baumannii to the human host. Moreover, the single and double mutants exhibited increased antibiotic resistances indicating a link between the two dioxygenases and antibiotic resistance.
Calcium (Ca2+) elevation is an essential secondary messenger in many cellular processes, including disease progression and adaptation to external stimuli, e.g., gravitational load. Therefore, mapping and quantifying Ca2+ signaling with a high spatiotemporal resolution is a key challenge. However, particularly on microgravity platforms, experiment time is limited, allowing only a small number of replicates. Furthermore, experiment hardware is exposed to changes in gravity levels, causing experimental artifacts unless appropriately controlled. We introduce a new experimental setup based on the fluorescent Ca2+ reporter CaMPARI2, onboard LED arrays, and subsequent microscopic analysis on the ground. This setup allows for higher throughput and accuracy due to its retrograde nature. The excellent performance of CaMPARI2 was demonstrated with human chondrocytes during the 75th ESA parabolic flight campaign. CaMPARI2 revealed a strong Ca2+ response triggered by histamine but was not affected by the alternating gravitational load of a parabolic flight.
Vascular integrity is essential for organ homeostasis to prevent edema formation and infiltration of inflammatory cells. Long non-coding RNAs (lncRNAs) are important regulators of gene expression and often expressed in a cell type-specific manner. By screening for endothelial-enriched lncRNAs, we identified the undescribed lncRNA NTRAS to control endothelial cell functions. Silencing of NTRAS induces endothelial cell dysfunction in vitro and increases vascular permeability and lethality in mice. Biochemical analysis revealed that NTRAS, through its CA-dinucleotide repeat motif, sequesters the splicing regulator hnRNPL to control alternative splicing of tight junction protein 1 (TJP1; also named zona occludens 1, ZO-1) pre-mRNA. Deletion of the hnRNPL binding motif in mice (Ntras∆CA/∆CA) significantly repressed TJP1 exon 20 usage, favoring expression of the TJP1α- isoform, which augments permeability of the endothelial monolayer. Ntras∆CA/∆CA mice further showed reduced retinal vessel growth and increased vascular permeability and myocarditis. In summary, this study demonstrates that NTRAS is an essential gatekeeper of vascular integrity.
Previous studies towards reduced oxygen availability have mostly focused on changes in total mRNA expression, neglecting underlying transcriptional and post-transcriptional events. Therefore, we generated a comprehensive overview of hypoxia-induced changes in total mRNA expression, global de novo transcription, and mRNA stability in monocytic THP-1 cells. Since hypoxic episodes often persist for prolonged periods, we further compared the adaptation to acute and chronic hypoxia. While total mRNA changes correlated well with enhanced transcription during short-term hypoxia, mRNA destabilization gained importance under chronic conditions. Reduced mRNA stability not only added to a compensatory attenuation of immune responses, but also, most notably, to the reduction in nuclear-encoded mRNAs associated with various mitochondrial functions. These changes may prevent the futile production of new mitochondria under conditions where mitochondria cannot exert their full metabolic function and are indeed actively removed by mitophagy. The post-transcriptional mode of regulation might further allow for the rapid recovery of mitochondrial capacities upon reoxygenation. Our results provide a comprehensive resource of functional mRNA expression dynamics and underlying transcriptional and post-transcriptional regulatory principles during the adaptation to hypoxia. Furthermore, we uncover that RNA stability regulation controls mitochondrial functions in the context of hypoxia.