A naturally occurring transmissible spongiform encephalopathy (TSE) of mule deer was first reported in Colorado and Wyoming in 1967 and has since spread to other members of the cervid family in 22 ...states, 2 Canadian provinces, and the Republic of Korea. Chronic wasting disease (CWD), caused by exposure to an abnormally folded isoform of the cellular prion protein, is characterized by progressive neurological disease in susceptible natural and experimental hosts and is ultimately fatal. CWD is thought to be transmitted horizontally in excreta and through contaminated environments, features common to scrapie of sheep, though rare among TSEs. Evolving detection methods have revealed multiple strains of CWD and with continued development may lead to an effective antemortem test. Managing the spread of CWD, through the development of a vaccine or environmental cleanup strategies, is an active area of interest. As such, CWD represents a unique challenge in the study of prion diseases.
Pulmonary hypertension (PH) is a deadly vascular disease with enigmatic molecular origins. We found that vascular extracellular matrix (ECM) remodeling and stiffening are early and pervasive ...processes that promote PH. In multiple pulmonary vascular cell types, such ECM stiffening induced the microRNA-130/301 family via activation of the co-transcription factors YAP and TAZ. MicroRNA-130/301 controlled a PPARγ-APOE-LRP8 axis, promoting collagen deposition and LOX-dependent remodeling and further upregulating YAP/TAZ via a mechanoactive feedback loop. In turn, ECM remodeling controlled pulmonary vascular cell crosstalk via such mechanotransduction, modulation of secreted vasoactive effectors, and regulation of associated microRNA pathways. In vivo, pharmacologic inhibition of microRNA-130/301, APOE, or LOX activity ameliorated ECM remodeling and PH. Thus, ECM remodeling, as controlled by the YAP/TAZ-miR-130/301 feedback circuit, is an early PH trigger and offers combinatorial therapeutic targets for this devastating disease.
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•Matrix remodeling induces YAP/TAZ-miR-130/301 early in pulmonary hypertension (PH)•YAP/TAZ-miR-130/301 promotes matrix remodeling via a mechanoactive feedback loop•Such matrix remodeling drives pulmonary vascular activation and cellular crosstalk•Pharmacologic modulation of this circuit ameliorates matrix remodeling and PH
Bertero et al. establish vascular matrix remodeling as an early, pervasive driver of pulmonary hypertension (PH) controlled by mechanoactive feedback from YAP/TAZ-microRNA-130/301 in multiple cell types. Inhibition of this circuit ameliorated matrix remodeling and PH, thus introducing promising cooperative therapies to treat this disease.
Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled ...haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average minimum contig length needed to cover 50% of the genome: 26 million base pairs) integrate all forms of genetic variation, even across complex loci. We identified 107,590 structural variants (SVs), of which 68% were not discovered with short-read sequencing, and 278 SV hotspots (spanning megabases of gene-rich sequence). We characterized 130 of the most active mobile element source elements and found that 63% of all SVs arise through homology-mediated mechanisms. This resource enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1526 expression quantitative trait loci as well as SV candidates for adaptive selection within the human population.
In a book full of directly applicable lessons for policymakers, Haley J. Swedlund explores why foreign aid is delivered in different ways at different times, and why various approaches prove to be ...politically unsustainable. She finds that no aid-delivery mechanism has yet resolved commitment problems in the donor-recipient relationship; bargaining compromises break down and have to be renegotiated; frustration grows; new ways of delivering aid gain traction over existing practices; and the dance resumes.
Swedlund draws on hundreds of interviews with key decision makers representing both donor agencies and recipient governments, policy and archival documents in Ghana, Rwanda, Tanzania, and Uganda, and an original survey of top-level donor officials working across twenty countries in Sub-Saharan Africa. This wealth of data informs Swedlund's analysis of fads and fashions in the delivery of foreign aid and the interaction between effectiveness and aid delivery. The central message ofThe Development Danceis that if we want to know whether an aid delivery mechanism is likely to be sustained over the long term, we need to look at whether it induces credible commitments from both donor agencies and recipient governments over the long term.
Motivation
Budget support is the form of aid most commonly associated with recipient‐country ownership. However, a number of scholars and practitioners have criticized the approach as masking new ...forms of conditionality. Was budget support simply a guise for increasing donor influence in recipient countries? How can we explain the rapid shift towards budget support, as well as the rapid decline in its popularity after only a few years?
Purpose
We use a bargaining framework to explain the rise and fall of budget support. Contrary to explanations that suggest that budget support was a normative decision by donors designed to increase aid effectiveness by fostering ownership, a bargaining framework emphasizes that aid policy is the result of sustained negotiations between donors and recipients. These negotiations, however, are constrained by donors’ inability to deliver aid as promised.
Approach
We use a Nash bargaining framework to formalize the predictions of a bargaining model. From the model, two testable predictions emerge: (1) in exchange for more credible commitments, recipient governments are willing to selectively offer donor agencies greater access to and influence over domestic policy decision‐making; and (2) in exchange for such influence, donor agencies are willing to exert less pressure on recipients to be politically inclusive. We then test the implications of the model using case‐study evidence from Rwanda and Tanzania.
Findings
The empirical data, based on over 80 interviews with practitioners over several periods of research in both countries, provide substantial evidence in support of the model’s core assumptions and predictions. Contrary to claims that budget support increased recipient‐country ownership, interviews (identified as personal communications) suggest that, in exchange for more credible commitments, recipient governments were willing to grant donors greater access and influence. In return, donor agencies reduced demands on the recipient government regarding political inclusivity, tacitly accepting arrangements that centralized decision‐making and excluded civil society. When donor agencies could no longer provide budget support as promised, these negotiated arrangements broke down.
Policy Implications
The findings challenge a common narrative that donors embraced budget support because of a normative commitment to ownership. They also demonstrate the value of a bargaining framework. To understand why particular forms of aid, like budget support, rise in popularity only to quickly fall by the wayside, we need to understand what donor agencies and recipient governments bargain over and why.
The purpose of this study was to characterize COVID-19 content posted by users and disseminated via TikTok, a social media platform that has become known largely as an entertainment platform for ...viral video-sharing. We sought to capture how TikTok videos posted during the initial months of the COVID pandemic changed over time as cases accelerated.
This study is an observational analysis of sequential TikTok videos with #coronavirus from January to March 2020. Videos were independently coded to assess content (e.g., health relatedness, humor, fear, empathy), misinformation, and public sentiment. To assess engagement, we also codified how often videos were shared relative to their content.
We coded 750 videos and approximately one in four videos tagged with #coronavirus featured health-related content such as featuring objects such as face masks, hand sanitizer, and other cleaning products. Most videos evoked “humor/parody,” whereas 15% and 6% evoked “fear” and “empathy”, respectively. TikTok videos posted in March 2020 had the largest number of shares and comments compared with January and February 2020. The proportion of shares and comments for “misleading and incorrect information” featured in videos was lower in March than in January and February 2020. There was no statistical difference between the share and comment counts of videos coded as "incorrect/incomplete" and "correct" over the entire time period.
Analyzing readily available social media platforms, such as TikTok provides real-time insights into public views, frequency and types of misinformation, and norms toward COVID-19. Analyzing TikTok videos has the potential to be used to inform public health messaging and public health mitigation strategies.
Next generation sequencing (NGS), or massively paralleled sequencing, refers to a collective group of methods in which numerous sequencing reactions take place simultaneously, resulting in enormous ...amounts of sequencing data for a small fraction of the cost of Sanger sequencing. Typically short (50–250 bp), NGS reads are first mapped to a reference genome, and then variants are called from the mapped data. While most NGS applications focus on the detection of single nucleotide variants (SNVs) or small insertions/deletions (indels), structural variation, including translocations, larger indels, and copy number variation (CNV), can be identified from the same data. Structural variation detection can be performed from whole genome NGS data or “targeted” data including exomes or gene panels. However, while targeted sequencing greatly increases sequencing coverage or depth of particular genes, it may introduce biases in the data that require specialized informatic analyses. In the past several years, there have been considerable advances in methods used to detect structural variation, and a full range of variants from SNVs to balanced translocations to CNV can now be detected with reasonable sensitivity from either whole genome or targeted NGS data. Such methods are being rapidly applied to clinical testing where they can supplement or in some cases replace conventional fluorescence in situ hybridization or array-based testing. Here we review some of the informatics approaches used to detect structural variation from NGS data.
Salmonella outbreaks from contaminated water and nonanimal foods (e.g., produce) are increasingly reported. To address the environment as a potential source of pathogenic Salmonella, we investigated ...levels of salmonellae and the geographic and temporal variation of Salmonella serotypes from surface waters in a region of Georgia (United States) with a history of high salmonellosis case rates. Monthly water samples were collected from six stations in the Little River (Upper Suwannee Basin) for 12 months (April 2005 to April 2006). Salmonellae were enumerated using a three-step most-probable-number (MPN) assay. Salmonellae were detected in 57 of the 72 water samples collected (79.2%). Monthly Salmonella densities ranged from an MPN of 2.5 liter⁻¹ in April 2005 to 36.3 liter⁻¹ in August 2005; concentrations were significantly higher in the summer months compared to other seasons (P < 0.05). Concentrations were not significantly different between stations. Levels of salmonellae were correlated with average daily watershed rainfall for the 1 and 2 days preceding each sample collection (r = 0.77 and 0.68, respectively; P < 0.005). Additionally, water temperature was also positively associated with total Salmonella levels (r = 0.44; P < 0.05). In total, 13 S. enterica serotypes were identified among 197 Salmonella isolates. Eighty (40.6%) were identified as S. enterica subsp. arizonae. Muenchen and Rubislaw were the most frequently identified serotypes of the remaining 117 isolates (28 and 26 isolates, respectively). Serotype diversity peaked in the summer, with 9 serotypes observed in August compared to only one serotype (S. enterica subsp. arizonae) observed in April (2005 and 2006) (P < 0.05). Furthermore, all samples collected in August (6/6) contained multiple serotypes (two to five per sample). The results of this study suggest that Salmonella abundance and diversity in the environment vary temporally and are strongly influenced by seasonal precipitation and water temperature.
Next-generation sequencing (NGS) has emerged as a powerful technique for the detection of genetic variants in the clinical laboratory. NGS can be performed using DNA from FFPE tissue, but it is ...unknown whether such specimens are truly equivalent to unfixed tissue for NGS applications. To address this question, we performed hybridization-capture enrichment and multiplexed Illumina NGS for 27 cancer-related genes using DNA from 16 paired fresh-frozen and routine FFPE lung adenocarcinoma specimens and conducted extensive comparisons between the sequence data from each sample type. This analysis revealed small but detectable differences between FFPE and frozen samples. Compared with frozen samples, NGS data from FFPE samples had smaller library insert sizes, greater coverage variability, and an increase in C to T transitions that was most pronounced at CpG dinucleotides, suggesting interplay between DNA methylation and formalin-induced changes; however, the error rate, library complexity, enrichment performance, and coverage statistics were not significantly different. Comparison of base calls between paired samples demonstrated concordances of >99.99%, with 96.8% agreement in the single-nucleotide variants detected and >98% accuracy of NGS data when compared with genotypes from an orthogonal single-nucleotide polymorphism array platform. This study demonstrates that routine processing of FFPE samples has a detectable but negligible effect on NGS data and that these samples can be a reliable substrate for clinical NGS testing.
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