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Abstract Background Aging in postmitotic tissues is associated with clonal expansion of somatic mitochondrial deletions, the origin of which is not well understood. Such deletions are often flanked by direct nucleotide repeats, but this alone does not fully explain their distribution. Here, we hypothesized that the close proximity of direct repeats on single-stranded mitochondrial DNA (mtDNA) might play a role in the formation of deletions. Results By analyzing human mtDNA deletions in the major arc of mtDNA, which is single-stranded during replication and is characterized by a high number of deletions, we found a non-uniform distribution with a “hot spot” where one deletion breakpoint occurred within the region of 6–9 kb and another within 13–16 kb of the mtDNA. This distribution was not explained by the presence of direct repeats, suggesting that other factors, such as the spatial proximity of these two regions, can be the cause. In silico analyses revealed that the single-stranded major arc may be organized as a large-scale hairpin-like loop with a center close to 11 kb and contacting regions between 6–9 kb and 13–16 kb, which would explain the high deletion activity in this contact zone. The direct repeats located within the contact zone, such as the well-known common repeat with a first arm at 8470–8482 bp (base pair) and a second arm at 13,447–13,459 bp, are three times more likely to cause deletions compared to direct repeats located outside of the contact zone. A comparison of age- and disease-associated deletions demonstrated that the contact zone plays a crucial role in explaining the age-associated deletions, emphasizing its importance in the rate of healthy aging. Conclusions Overall, we provide topological insights into the mechanism of age-associated deletion formation in human mtDNA, which could be used to predict somatic deletion burden and maximum lifespan in different human haplogroups and mammalian species.

BackgroundThe anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug.MethodsOptical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals (n = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the following OCT measurements: (1) average ppRNFL, (2) inferior quadrant, (3) nasal quadrant, (4) superior quadrant, (5) temporal quadrant, (6) inferior nasal sector, (7) nasal inferior sector, (8) superior nasal sector, and (9) nasal superior sector. Using the summary statistics from the GWAS analyses we conducted gene-based testing using VEGAS2. We conducted nine different PRS analyses using the OCT measurements. To determine if VGB-exposed individuals were predisposed to having a thinner RNFL, we calculated their polygenic burden for retinal thickness. PRS alleles for retinal thickness were calculated using published summary statistics from a large-scale GWAS of inner retinal morphology using the OCT images of UK Biobank participants.ResultsThe GWAS analyses did not identify a significant association after correction for multiple testing. Similarly, the gene-based and PRS analyses did not reveal a significant association that survived multiple testing.ConclusionWe set out to identify common genetic predictors for VGB induced ppRNFL thinning. Results suggest that large-effect common genetic predictors are unlikely to exist for ppRNFL thinning (as a marker of VAVFL). Sample size was a limitation of this study. However, further recruitment is a challenge as VGB is rarely used today because of this adverse reaction. Rare variants may be predictors of this adverse drug reaction and were not studied here.

Mitochondrial DNA (mtDNA) is particularly vulnerable to somatic mutagenesis. Potential mechanisms include DNA polymerase γ (POLG) errors and the effects of mutagens, such as reactive oxygen species. Here, we studied the effects of transient hydrogen peroxide (H2O2 pulse) on mtDNA integrity in cultured HEK 293 cells, applying Southern blotting, ultra-deep short-read and long-read sequencing. In wild-type cells, 30 min after the H2O2 pulse, linear mtDNA fragments appear, representing double-strand breaks (DSB) with ends characterized by short GC stretches. Intact supercoiled mtDNA species reappear within 2–6 h after treatment and are almost completely recovered after 24 h. BrdU incorporation is lower in H2O2-treated cells compared to non-treated cells, suggesting that fast recovery is not associated with mtDNA replication, but is driven by rapid repair of single-strand breaks (SSBs) and degradation of DSB-generated linear fragments. Genetic inactivation of mtDNA degradation in exonuclease deficient POLG p.D274A mutant cells results in the persistence of linear mtDNA fragments with no impact on the repair of SSBs. In conclusion, our data highlight the interplay between the rapid processes of SSB repair and DSB degradation and the much slower mtDNA re-synthesis after oxidative damage, which has important implications for mtDNA quality control and the potential generation of somatic mtDNA deletions.

Epilepsy and mental retardation are known to be associated with pathogenic mutations in a broad range of genes that are expressed in the brain and have a role in neurodevelopment. Here, we report on a family with three affected individuals whose clinical symptoms closely resemble a neurodevelopmental disorder. Whole-exome sequencing identified a homozygous stop-gain mutation, p.Gln19*, in the BATF2 gene in the patients. The BATF2 transcription factor is predominantly expressed in macrophages and monocytes and has been reported to modulate AP-1 transcription factor-mediated pro-inflammatory responses. Transcriptome analysis showed altered base-level expression of interferon-stimulated genes in the patients’ blood, typical for type I interferonopathies. Peripheral blood mononuclear cells from all three patients demonstrated elevated responses to innate immune stimuli, which could be reproduced in CRISPR–Cas9-generated BATF2−/− human monocytic cell lines. BATF2 is, therefore, a novel disease-associated gene candidate for severe epilepsy and mental retardation related to dysregulation of immune responses, which underscores the relevance of neuroinflammation for epilepsy.

Aims: Studies demonstrated that oxidized fish oil (OFO) promoted oxidative stress and induced mitochondrial dysfunction and lipotoxicity, which attenuated beneficial effects of fish oil supplements in the treatment of nonalcoholic fatty liver disease (NAFLD). The current study was performed on yellow catfish, a good model to study NAFLD, and its hepatocytes to explore whether selenium (Se) could alleviate OFO-induced lipotoxicity via the inhibition of oxidative stress and determine its potential mechanism. Results: The analysis of triglycerides content, oxidative stress parameters, and histological and transmission electronic microscopy observation showed that high dietary Se supplementation alleviated OFO-induced lipotoxicity, oxidative stress, and mitochondrial injury and dysfunction. RNA-sequencing and immunoblotting analysis indicated that high dietary Se reduced OFO-induced decline of peroxisome-proliferator-activated receptor alpha (Pparα) and ubiquitin-specific protease 4 (Usp4) protein expression. High Se supplementation also alleviated OFO-induced reduction of thioredoxin reductase 2 (txnrd2) messenger RNA (mRNA) expression level and activity. The txnrd2 knockdown experiments revealed that txnrd2 mediated Se- and oxidized eicosapentaenoic acid (oxEPA)-induced changes of mitochondrial reactive oxygen species (mtROS) and further altered Usp4 mediated-deubiquitination and stabilization of Pparα, which, in turn, modulated mitochondrial fatty acid β-oxidation and metabolism. Mechanistically, Usp4 deubiquitinated Pparα and ubiquitin-proteasome-mediated Pparα degradation contributed to oxidative stress-induced mitochondrial dysfunction. Innovation: These findings uncovered a previously unknown mechanism by which Se and OFO interacted to affect lipid metabolism via the Txnrd2-mtROS-Usp4-Pparα pathway, which provides the new target for NAFLD prevention and treatment. Conclusion: Se ameliorated OFO-induced lipotoxicity via the inhibition of mitochondrial oxidative stress, remodeling of Usp4-mediated deubiquitination, and stabilization of Pparα. Antioxid. Redox Signal. 40, 433–452. [ABSTRACT FROM AUTHOR]

Background: The anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug. Methods: Optical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals (n = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the following OCT measurements: (1) average ppRNFL, (2) inferior quadrant, (3) nasal quadrant, (4) superior quadrant, (5) temporal quadrant, (6) inferior nasal sector, (7) nasal inferior sector, (8) superior nasal sector, and (9) nasal superior sector. Using the summary statistics from the GWAS analyses we conducted gene-based testing using VEGAS2. We conducted nine different PRS analyses using the OCT measurements. To determine if VGBexposed individuals were predisposed to having a thinner RNFL, we calculated their polygenic burden for retinal thickness. PRS alleles for retinal thickness were calculated using published summary statistics from a large-scale GWAS of inner retinal morphology using the OCT images of UK Biobank participants. Results: The GWAS analyses did not identify a significant association after correction for multiple testing. Similarly, the gene-based and PRS analyses did not reveal a significant association that survived multiple testing. Conclusion: We set out to identify common genetic predictors for VGB induced ppRNFL thinning. Results suggest that large-effect common genetic predictors are unlikely to exist for ppRNFL thinning (as a marker of VAVFL). Sample size was a limitation of this study. However, further recruitment is a challenge as VGB is rarely used today because of this adverse reaction. Rare variants may be predictors of this adverse drug reaction and were not studied here. [ABSTRACT FROM AUTHOR]

Abstract Background Chronic venous insufficiency (CVI) is a common disease with a high prevalence. Incompetent venous valves are considered as one of the main causes. Besides compression therapy, various surgical therapies are practiced, whereby the reconstruction of valves is of central importance. There is an unmet clinical need, no valve prosthesis is commercially available to date. This work introduces two versions of a patented prosthetic bicuspid valve design made of electrospun thermoplastic silicone polycarbonate polyurethane (TSPCU) nanofiber leaflets attached in a nitinol stent, and their performance in static and pulsatile operation. Results The valves mainly fulfill the requirements widely accepted in literature. Valves of both versions were functional in the physiological pressure range up to 50 mmHg with design specific differences. Conclusions The here introduced design versions act as a platform technology and can be tailored for an intended implantation site. Evaluation of the original and modified valve concept demonstrated efficacy, with limitations at higher loads for original design. At the current state, the modification is preferable for fabrication, as one processing step is eliminated. Moreover, specific design recommendations could be drawn for valves of similar basic structure. Future work will focus on long-term performance and biocompatibility prior to the initiation of preclinical in vivo studies.

Abstract Background To investigate the artifact sizes of four common breast clip-markers on a standard breast magnetic resonance imaging (MRI) protocol in an in vitro phantom model. Methods Using 1.5-T and 3-T whole-body scanners with an 18-channel breast coil, artifact dimensions of four breast biopsy markers in an agarose-gel phantom were measured by two readers on images obtained with the following sequences: T2-weighted fast spin-echo short inversion time fat-suppressed inversion-recovery with magnitude reconstruction (T2-TIRM); T1-weighted spoiled gradient-echo with fat suppression (T1_FL3D), routinely used for dynamic contrast-enhanced imaging; diffusion-weighted imaging (DWI), including a readout segmented echo-planar imaging (RESOLVE-DWI) and echo-planar imaging sequence (EPI-DWI). After outlining the artifacts by freehand regions of interest, sagittal and lateral diameters in axial images were measured. Results Interreader agreement for artifact size quantification was high, depending on the sequence (80.4–94.8%). Overall, the size, shape, and appearance of artifacts depended on clip type and MRI sequence. The artifact size ranged from 5.7 × 8.5 mm2 to 13.4 × 17.7 mm2 at 1.5 T and from 6.6 × 8.2 mm2 to 17.7 × 20.7 mm2 at 3 T. Clip artifacts were largest on EPI-DWI and RESOLVE-DWI (p ≤ 0.016). In three out of four clips, T2-TIRM showed the smallest artifact (p ≤ 0.002), while in one clip the artifact was smallest on T1_FL3D (p = 0.026). With the exception of one clip in the RESOLVE sequence, all clips showed a decrease in the artifact area from DWI to ADC images (p ≤ 0.037). Conclusion Breast clip-marker MRI artifact appearances depend on clip type, field strength, and sequence and may reach a significant size, potentially obscuring smaller lesions and hindering accurate assessment of breast tumors. Relevance statement Considerable variations in artifact size and characteristics across different breast clips, MRI sequences, and field strengths exist. Awareness of these artifacts and their characteristics is essential to ensure accurate interpretation of scans and appropriate treatment planning. Key Points Awareness of breast clip artifacts is essential for accurate interpretation of MRI. The appearance of artifacts depends on breast clip type, field strength, and sequence. Clip-related artifacts might hinder the visibility of small lesions. Graphical Abstract

Abstract The dopamine reward prediction error signal is known to be subjective but has so far only been assessed in aggregate choices. However, personal choices fluctuate across trials and thus reflect the instantaneous subjective reward value. In the well-established Becker-DeGroot-Marschak (BDM) auction-like mechanism, participants are encouraged to place bids that accurately reveal their instantaneous subjective reward value; inaccurate bidding results in suboptimal reward (“incentive compatibility”). In our experiment, male rhesus monkeys became experienced over several years to place accurate BDM bids for juice rewards without specific external constraints. Their bids for physically identical rewards varied trial by trial and increased overall for larger rewards. In these highly experienced animals, responses of midbrain dopamine neurons followed the trial-by-trial variations of bids despite constant, explicitly predicted reward amounts. Inversely, dopamine responses were similar with similar bids for different physical reward amounts. Support Vector Regression demonstrated accurate prediction of the animals’ bids by as few as twenty dopamine neurons. Thus, the phasic dopamine reward signal reflects instantaneous subjective reward value.

Abstract Recent years have witnessed signs of increasing political instability in democratic countries as well as growing alienation from civic institutions and processes among citizens, especially among young people. Within the context of civic and citizenship education, it is important to review such phenomena and study their extent among young people as well as the factors that have the potential of promoting different forms of citizenship engagement. Using data from the International Civic and Citizenship Education Study (ICCS) 2016 and 2009, this article provides insights into the expectations of young people to actively engage as citizens in the future and what influences these expectations, with a primary focus on the role of civic knowledge and trust in civic institutions. Results from ICCS 2009 and 2016 show that while large majorities among young people expected to vote in elections, only relatively few found it likely to be more actively involved in political action. Except for engagement in illegal protest, young people’s expected participation in general appeared to be positively related to trust. However, associations with civic knowledge were more differentiated. Trust and civic knowledge tended to have negative correlations in countries with higher levels of perceived corruption, while a different association became apparent in democracies with more transparent institutions. Civic knowledge was consistently positively related to anticipated voting while it was negatively related to expected illegal protest. More knowledgeable students were also less inclined to consider active (conventional) forms of political participation in the future.

Abstract Religious attachment has been identified as an important correlate of civic participation, civic engagement, and civil participation among adults. This study investigates two aspects of relationships between religiosity and intended political engagement among lower secondary school students in 2009 and 2016. One aspect is the extent to which religious attachment is associated with an endorsement of the influence of religion in society. This can be viewed as the converse of secularity which asks for the separation of social and political institutions from religion. A second aspect investigated is the extent to which religious attachment is associated with expected adult electoral participation and expected adult active political participation after controlling for the effects of other characteristics. While the results from this study show no strong or consistent relationships between religious background and expected political participation among lower-secondary students, findings suggest that young people’s endorsement of religious influence in society depends strongly on their religious background and in turn shows associations with expected active political participation.

There are various electromagnetic (EM) field theories of consciousness. They postulate an epineural EM field which, due to its binding properties, unifies the different neuronal information differences originating from various sensory and cognitive processes. Only through a real physical integration in space within this field could phenomenal consciousness arise. This would solve the binding problem mentioned in the philosophy of mind. On closer inspection, the electromagnetic interaction not only provides an explanation for the integrative property of the EM field, but also for the necessary differentiating contrasts of information. This article will take a closer look at the physical properties of a postulated EM field. It will also show how the problem of qualia in connection with emergentism could be solved by a new variant of EM field theory. If it can be clearly demonstrated that the postulated epineural EM field plays a decisive role in the origin of consciousness in addition to neuronal “wired” information processing, this also leaves less room for metaphysical assumptions that attempt to solve the binding problem. In experiments to prove the postulated epineural EM field by means of external electromagnetic manipulations, it can never be ruled out that these also have a direct effect on the “wired” neuronal signal processing. Therefore, on the way to proving the EM field theory of consciousness, an experimental method is needed that must ensure that external manipulations only affect the extensions of the EM field without directly influencing the neuronal network. A method will be discussed here that works with the shielding of EM fields instead of external electromagnetic stimuli.