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Targeting Cis-regulatory elements for CRISPR-mediated transcriptional activation of the human MIR503HG locus
Get PDFAdvances in genome annotation have revealed a striking increase in the number and complexity of non-coding RNA (ncRNA) genes, particularly multi-transcript loci that harbor long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) within the same genomic region. These loci can often function as coordinated regulatory units, with their transcription modulated by shared cis-acting regulatory elements (CREs). Traditional gene manipulation approaches, which typically target individual transcripts, are insufficient to capture the full regulatory and therapeutic potential of these complex loci. Here, we present “cis-ON” a single-vector lentiviral delivery system based on CRISPR activation (CRISPRa), designed to simultaneously upregulate multiple noncoding RNA transcripts by targeting a single CRE.We focused on the evolutionarily conserved MIR503HG locus, which encodes seven lncRNA isoforms and hosts the miR-424/503 cluster, both implicated in various cellular processes, including proliferation, angiogenesis, and endothelial-to-mesenchymal transition. Using integrative analysis of histone marks (H3K27Ac, H3K4Me3), DNase hypersensitivity, and CAGE-seq data, we identified the primary promoter of the MIR503HG locus. A dual fluorescent reporter screen selected optimal single guide RNAs (sgRNAs) for targeting this region. We then engineered cis-ON, a novel lentiviral system combining dCas9-VPR and sgRNA to enable a streamlined single-vector delivery approach. Transduction of primary human endothelial cells with this system robustly activated the entire locus including the MIR503HG isoforms and co-embedded miRNAs miR-424 and miR-503, demonstrating coordinated transcriptional regulation. Additionally, the neighboring LINC00629 lncRNA locus remained unaffected, highlighting regulatory specificity.This approach demonstrates the feasibility of modulating complex ncRNA loci across a ∼ 10 kb genomic region by targeting a single CRE, bypassing limitations of transcriptspecific strategies. By enabling simultaneous upregulation of lncRNAs and miRNAs, the cis-ON platform provides a streamlined strategy for restoring regulatory networks disrupted in disease
Trust, but verify:Managerial ability and conditional accounting conservatism
Get PDFHigh-ability managers’ performance track records and “integrity” culture foster capital providers’ trust and reduce career risks, allowing them to set the firm’s financial reporting policies. Employing this discretion, high-ability managers are likely to report less conditionally conservative earnings. Data from S&P 1500 U.S. firms between 1996 and 2017 support this conjecture. Additional analysis continues to suggest that high-ability managers lower conditional accounting conservatism under limited boundary conditions. We also document that some high-ability managers misuse their financial reporting discretion opportunistically. Despite this, using a two-stage method, we show that our proposed theoretical mechanism—firms with a stronger corporate integrity culture, which promotes trust—enables high-ability managers to report less conditionally conservatively. This study contributes to the research on accounting conservatism and managerial behavior, cautioning capital providers against placing excessive trust in high-ability managers, as in some cases, that trust has been found to be misplaced
Heatwaves amplify air pollution risks in Sub-Saharan Africa
Get PDFMounting evidence demonstrates that heatwaves aggravate urban air pollution, with substantial impacts on public health, but comparatively little research has addressed Sub-Saharan African contexts. In this study, we focused on Kigali, Rwanda, to assess the relationship between extreme heat events and concentrations of fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) from 2021 to 2024. Using low-cost sensors for dense spatiotemporal coverage, our analysis finds that O3 concentrations increased significantly during 6 heatwave events with peak values up to 40% higher during heatwaves. Heatwaves also resulted in spikes in PM2.5 and NO2, however the diurnal and seasonal analyses showed that PM2.5 and NO2 dynamics were shaped more by local emissions than temperature alone. These results highlight the compound risks of heat and air pollution in sub-Saharan African cities, underscoring the importance of early-warning systems and robust urban policies that account for both heat and air pollution. In addition, the atmospheric dynamics identified in this research differ from those observed in many high-income countries, highlighting a critical need for more research exploring the intersection of heat and air pollution in Sub-Saharan Africa
The Protein Design Archive (PDA): insights from 40 years of protein design
Get PDFThe field of protein design has changed dramatically over the last 40 years, with a range of methods developing from rational design to more recent data-driven approaches. While considerable insight could be gained from analysing designed proteins, there is no single resource that brings together all the relevant data, making it difficult to identify current challenges and opportunities within the field.Here we present the Protein Design Archive, a website and database of designed proteins. Using the database, we performed systematic analysis that reveals a rapid increase in the number and complexity of designs over time and uncovers biases in their amino-acid usage and secondary structure content. Finally, sequence- and structure-based analysis demonstrates the breadth and novelty of designs within the archive. The PDA will be a valuable resource for guiding development of protein design, helping the field reach its potential
Automated gait analysis indicates efficacy of T-type calcium channel inhibition for mitigation of disrupted calcium signalling in an SCA5 mouse model
Get PDFSpinocerebellar ataxias (SCAs) are dominantly inherited progressive neurodegenerative disorders which to date have no effective treatment. SCA5 arises from mutations in the β-III spectrin gene (SPTBN2) with mice lacking β-III spectrin function (β-III−/−) mirroring the human clinical phenotype. This study finds evidence for dysregulated calcium homeostasis in β-III−/− mice as evidenced by enhanced auto-phosphorylation of calcium-calmodulin dependent kinase II (CaMKII), a major calcium sensor in cells, and phosphorylation of several CaMKII targets. Mibefradil, an inhibitor of calcium channels, was also found to improve disordered β-III−/− Purkinje cell dendritic morphology in vitro. However, key to evaluation of potential treatments in vivo is the ability to assess relevant changes at later stages of disease in β-III−/− mice, which has previously been problematic. Here the CatWalk XT system was successful in detecting differences in both truncal stability and interlimb coordination across the disease course of β-III−/− mice. Building on these findings CatWalk analysis showed trimethadione, a selective T-type calcium channel inhibitor, but not riluzole nor verapamil, significantly improved interlimb coordination of 8-month-old β-III−/− mice. These findings highlight the CatWalk XT system as a valuable tool to assess age-dependence of motor function and that modulation of T-type calcium channels has therapeutic potential for SCAs
Dark trading and stock-based CEO pay
Get PDFDoes trading away from public exchanges affect the way top executives are paid? Yes, our study finds that companies with a higher proportion of shares traded in “dark” (i.e., off-exchange) venues tend to offer more stock-based compensation to their CEOs. This relationship is primarily driven by enhanced price informativeness in lit (i.e., on-exchange/public) markets resulting from dark trading activities, making stock-based compensation a more attractive and effective tool for aligning executive incentives with shareholder returns. Consistent with this explanation, we show that the effect is most pronounced in firms where the impact of dark trading is likely greatest on price informativeness (firms with opaque information environments) and where compensation committees are more likely to extract information from stock prices (committees possessing greater financial expertise, higher equity ownership, and fewer external commitments). To address endogeneity concerns, we employ a treatment effects model and a difference-in-differences framework using the SEC's Tick Size Pilot Program as an exogenous shock to dark trading.</p
Multiplex Nodal Modularity: A novel network metric for the regional analysis of amnestic mild cognitive impairment during a working memory binding task
No full textModularity is a well-established concept for assessing community structures in various single and multi-layer networks, including those in biological and social domains. Brain networks are known to exhibit community structure at local, meso, and global scale. However, modularity is limited as a metric to a global scale describing the overall strength of community structure, overlooking important variations in community structure at node level. To address this limitation, we extended modularity to individual nodes. This novel measure of nodal modularity (nQ) captures both mesoscale and local-scale changes in modularity. We hypothesized that nQ would illuminate granular changes in the brain due to diseases such as Alzheimer's disease (AD), which are known to disrupt the brain's modular structure. We explored nQ in multiplex networks of a visual short-term memory binding task in fMRI and DTI data in the early stages of AD. While limited by sample size, changes in nQ for individual regions of interest (ROIs) in our fMRI networks were predominantly observed in visual, limbic, and paralimbic systems in the brain, aligning with known AD trajectories and linked to amyloid- and tau deposition. Furthermore, observed changes in white-matter microstructure in our DTI networks in parietal and frontal regions may compliment studies of white-matter integrity in poor memory binders. Additionally, nQ clearly differentiated MCI from MCI converters indicating that nQ may be sensitive to this key turning point of AD. Our findings demonstrate the utility of nQ as a measure of localized group structure, providing novel insights into task and disease-related variability at the node level. Given the widespread application of modularity as a global measure, nQ represents a significant advancement, providing a granular measure of network organization applicable to a wide range of disciplines
Designing better gene therapies for lysosomal storage disorders using engineered enzymes
No full textChatGPT’s interpretation of contested memoryscapes favours the voice of current governments, capitalism and the far-right
No full textThis study examines political biases in ChatGPT-4o’s interpretations of memoryscapes linked to dictatorial regimes in Spanish-speaking countries. Using a least-to-most prompting model and a Discourse-Historical Approach (DHA), we analysed responses in both Spanish and English about three key memorial sites: the Valley of the Fallen (Spain), the ESMA Museum and Site of Memory (Argentina), and the Monument to Salvador Allende (Chile). Findings show a preference for dominant, capitalist, and government-aligned perspectives, often reinforced by far-right rhetoric, particularly in Spanish language. The research highlights generative AI’s influence in shaping heritage narratives and the challenges of ensuring unbiased and multi-vocal outputs. This study advances the fields of cultural heritage, digital humanities, and education, while also shedding light on the wider implications of ChatGPT’s outputs for memory politics and democratic governance.</p
Metagenomics reveals fibre fermentation and AMR pathways in red grouse (Lagopus scotica) microbiota
No full textBACKGROUND: The avian caecal microbiota plays a vital role in host nutrition, enabling non-digestible, fibrous material to be converted into compounds that can be absorbed and used as an energy source by the host. The diet of adult red grouse ( Lagopus scotica) is dominated by heather ( Calluna vulgaris), which is particularly high in fibre. It is therefore likely that the caecal microbiota plays a key role in enabling grouse to thrive on this diet. In this study, we present the first characterisation of the caecal microbiota of red grouse using modern sequencing methods. RESULTS: We performed metagenomic sequencing on caecal content samples from fifteen red grouse from three upland estates in Scotland. From this data, we constructed and characterised twelve high-quality, species-level metagenome assembled genomes (MAGs). Eleven of these MAGs could not be assigned a taxonomic label at species level, indicating that they may be novel species. MAGs belonged to diverse taxa (5 phyla) and several encoded genes and pathways for the digestion of fibres, including cellulose, hemi-cellulose, xylooligosaccharides and pectin. Several MAGs also contained antimicrobial resistance genes, predominantly related to vancomycin resistance.CONCLUSIONS: This study is the first to reconstruct commensal microbial genomes from red grouse. The caeca contain diverse, often novel, microbial taxa capable of fermenting various fibres, potentially aiding in the digestion of the red grouse’s high-fibre diet. Further research is necessary to explore how these bacteria support red grouse nutrition and health.SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12866-025-04280-1.</p
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