Measuring transcription factor binding and gene expression using barcoded self-reporting transposon calling cards and transcriptomes

Calling cards technology using self-reporting transposons enables the identification of DNA-protein interactions through RNA sequencing. Although immensely powerful, current implementations of calling cards in bulk experiments on populations of cells are technically cumbersome and require many replicates to identify independent insertions into the same genomic locus. Here, we have drastically reduced the cost and labor requirements of calling card experiments in bulk populations of cells by introducing a DNA barcode into the calling card itself. An additional barcode incorporated during reverse transcription enables simultaneous transcriptome measurement in a facile and affordable protocol. We demonstrate that barcoded self-reporting transposons recove

Newspaper coverage of food insecurity in UK, 2016–2019: a multi-method analysis

Abstract: Background: Food insecurity is a growing concern in the UK. Newspaper coverage can reflect and shape public and political views. We examined how frequently food insecurity was reported on in UK newspapers, how the problem and its drivers were described, and which solutions were proposed. Methods: Using Factiva, we searched for news articles that were substantively about food insecurity and published in national UK newspapers between 01 January 2016 and 11 June 2019. We examined whether the number of articles differed over the study period, and conducted a thematic analysis to theoretical saturation using a random sample of articles. Results: Overall, 436 articles met our inclusion criteria and 132 (30%) were analysed thematically. Reporting was more prevalent in the summer, with mentions of ‘holiday hunger’ among children, and leading up to Christmas, when charity was encouraged. Articles often contained views from advocacy groups and charities, who appeared to play an important role in maintaining news interest in food insecurity. From the thematic analysis, we developed themes related to the problems (‘definitions of food insecurity’ and ‘consequences of food insecurity for individuals’), drivers (‘insufficient income as an immediate driver’ and ‘government versus individual responsibility’), and solutions (‘charitable food aid’ and ‘calls for government action’). The problem of food insecurity was often defined by food bank use or hunger, but other definitions and a range of consequences for individuals were acknowledged. Articles identified government as a driver of food insecurity, especially in relation to the roll-out of Universal Credit. Few articles proposed individual failings as a driver of food insecurity. The reported existing solutions predominantly focused on food banking and redistributing ‘food waste’. The public, charities, and individuals experiencing food insecurity were generally portrayed as supportive of government action to tackle food insecurity. However, contention within government regarding the extent of food insecurity, governmental responsibility and potential solutions was reported. Conclusions: Food insecurity was a topic of significant interest within UK newspapers. Newspapers were used to call for government action and advocate for structural, income-based solutions

Investigating the impact of TB case-detection strategies and the consequences of false positive diagnosis through mathematical modelling.

BACKGROUND: Increasing case notifications is one of the top programmatic priorities of National TB Control Programmes (NTPs). To find more cases, NTPs often need to consider expanding TB case-detection activities to populations with increasingly low prevalence of disease. Together with low-specificity diagnostic algorithms, these strategies can lead to an increasingly high number of false positive diagnoses, which has important adverse consequences. METHODS: We apply TIME, a widely-used country-level model, to quantify the expected impact of different case-finding strategies under two scenarios. In the first scenario, we compare the impact of implementing two different diagnostic algorithms (higher sensitivity only versus higher sensitivity and specificity) to reach programmatic screening targets. In the second scenario, we examine the impact of expanding coverage to a population with a lower prevalence of disease. Finally, we explore the implications of modelling without taking into consideration the screening of healthy individuals. Outcomes considered were changes in notifications, the ratio of additional false positive to true positive diagnoses, the positive predictive value (PPV), and incidence. RESULTS: In scenario 1, algorithm A of prolonged cough and GeneXpert yielded fewer additional notifications compared to algorithm B of any symptom and smear microscopy (n = 4.0 K vs 13.8 K), relative to baseline between 2017 and 2025. However, algorithm A resulted in an increase in PPV, averting 2.4 K false positive notifications thus resulting in a more efficient impact on incidence. Scenario 2 demonstrated an absolute decrease of 11% in the PPV as intensified case finding activities expanded into low-prevalence populations without improving diagnostic accuracy, yielding an additional 23 K false positive diagnoses for an additional 1.3 K true positive diagnoses between 2017 and 2025. Modelling the second scenario without taking into account screening amongst healthy individuals overestimated the impact on cases averted by a factor of 6. CONCLUSION: Our findings show that total notifications can be a misleading indicator for TB programme performance, and should be interpreted carefully. When evaluating potential case-finding strategies, NTPs should consider the specificity of diagnostic algorithms and the risk of increasing false-positive diagnoses. Similarly, modelling the impact of case-finding strategies without taking into account potential adverse consequences can overestimate impact and lead to poor strategic decision-making

FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury

The proximal tubule has a remarkable capacity for repair after acute injury, but the cellular lineage and molecular mechanisms underlying this repair response are incompletely understood. Here, we developed a Kim1-GFPCreERt2 knockin mouse line (Kim1-GCE) in order to perform genetic lineage tracing of dedifferentiated cells while measuring the cellular transcriptome of proximal tubule during repair. Acutely injured genetically labeled clones coexpressed KIM1, VIMENTIN, SOX9, and KI67, indicating a dedifferentiated and proliferative state. Clonal analysis revealed clonal expansion of Kim1+ cells, indicating that acutely injured, dedifferentiated proximal tubule cells, rather than fixed tubular progenitor cells, account for repair. Translational profiling during injury and repair revealed signatures of both successful and unsuccessful maladaptive repair. The transcription factor Foxm1 was induced early in injury, was required for epithelial proliferation in vitro, and was dependent on epidermal growth factor receptor (EGFR) stimulation. In conclusion, dedifferentiated proximal tubule cells effect proximal tubule repair, and we reveal an EGFR/FOXM1-dependent signaling pathway that drives proliferative repair after injury

Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease

The Next Generation Event Horizon Telescope Collaboration: History, Philosophy, and Culture

This white paper outlines the plans of the History Philosophy Culture Working Group of the Next Generation Event Horizon Telescope Collaboration.Comment: 23 pages, 1 figur

The Next Generation Event Horizon Telescope Collaboration: History, Philosophy, and Culture

This white paper outlines the plans of the History Philosophy Culture Working Group of the Next Generation Event Horizon Telescope Collaboration

Rethinking place-making: aligning placeness factors with perceived urban design qualities (PUDQs) to improve the built environment in historical district

Understanding the concept of place is critically important for urban design and place-making practice, and this research attempted to investigate the pathways by which perceived urban design qualities (PUDQs) influence placeness factors in the Chinese context. Twelve hypotheses were developed and combined in a structural equation model for validation. The Tanhualin historical district in Wuhan, China was selected for the analysis. As a result, place attachment was verified as a critical bridge factor that mediated the influence of PUDQs on place satisfaction. Among the five selected PUDQs, walkability and space quality were revealed as the most influential factors associated with place attachment and place satisfaction. Accessibility was actually indirectly beneficial to place-making via the mediation of walkability. Corresponding implications and strategies were discussed to maintain the sense of place for historic districts