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Unveiling molecular mechanisms of strobilurin resistance in the cacao pathogen Moniliophthora perniciosa
Get PDFStrobilurin fungicides inhibit mitochondrial respiration, leading to ATP depletion and oxidative stress. Although widely used in agriculture, these chemicals are ineffective against the cacao pathogen Moniliophthora perniciosa. Here, we show that M. perniciosa tolerates high concentrations of the commercial strobilurin azoxystrobin in vitro. Transcriptomic analysis revealed that short-term exposure triggers up-regulation of genes related to catabolic pathways, including the glyoxylate cycle and fatty acid degradation, alongside repression of genes involved in anabolic processes, such as cell division and ribosome biogenesis. Simultaneously, genes associated with cellular detoxification and oxidative stress responses were strongly induced. These alterations suggest that M. perniciosa remodels its metabolism to counteract fungicide toxicity. Remarkably, long-term exposure to azoxystrobin led to the emergence of a resistant mutant harboring mutations in two putative growth and transcriptional regulators. This work provides new insights into the molecular basis of strobilurin resistance and informs strategies for more effective fungicide deployment in agriculture
Fine-mapping genomic loci refines bipolar disorder risk genes
Get PDFBipolar disorder is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 bipolar disorder risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci and prioritized 17 likely causal SNPs for bipolar disorder. We mapped these SNPs to genes and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci and results from rare variant exome sequencing in bipolar disorder. Convergent lines of evidence supported the roles of genes involved in neurotransmission and neurodevelopment, including SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, FKBP2, RASGRP1, FURIN, FES, MED24 and THRA among others in bipolar disorder. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance of bipolar disorder polygenic risk scores across diverse populations and present a high-throughput fine-mapping pipeline
Genetic mapping in collaborative cross mouse strains identifies loci that affect initial sensitivity to cocaine
Get PDFRationale Cocaine use disorder (CUD) is a significant health concern that has devastating impacts on affected individuals and society. There are currently no approved therapies to treat CUD due, in part, to significant gaps in our knowledge about the underlying factors that increase risk. Individual genetic differences contribute to CUD risk. Identifying specific genetic mechanisms that increase risk could reveal novel targets for treatment and prevention. Objectives We identified two Collaborative Cross (CC) strains, CC004/TauUncJ (CC004) and CC041/TauUncJ (CC041), that differ significantly for locomotor response and self-administration of cocaine. In the current study, we used mapping crosses generated from both strains to identify genetic loci that are associated with behavioral responses to cocaine. Results We bred mice from the low (CC041) and high (CC004) responding strains to C57BL/6NJ mice to produce two F2 populations and identify genetic loci that influence locomotor response to cocaine. We identified three significant loci on chromosomes 7, 11 and 14 in the CC041 F2 mapping cross that collectively explain 14% of the phenotypic variance for locomotor response to cocaine. Bioinformatic analyses identified multiple genes on chromosomes 7 and 11 that are genetically plausible, have functional relevance and are suitable for further exploration. Conclusions Genetically defined and phenotypically divergent mouse strains are a useful tool for identifying candidate genes that influence behavioral responses to psychostimulants. Functional and mechanistic analyses of these genes could provide insights into biological processes that increase risk for CUD
Extensive differential gene expression and regulation by sex in human skeletal muscle
Get PDFThe identification of sex-differential gene regulatory elements is essential for understanding sex-differential patterns of health and disease. We leveraged bulk and single-nucleus RNA sequencing (RNA-seq) and single-nucleus ATAC-seq data from 281 skeletal muscle biopsies to characterize sex differences in gene expression and regulation at the cell-type and whole-tissue levels. We found highly concordant sex-biased expression of over 2,100 genes across the three muscle fiber types and bulk tissue. Gene pathways related to mitochondrial activity and energy metabolism were enriched for male-biased expression, whereas those related to signal transduction and cell differentiation were enriched for female-biased expression. We found widespread sex-biased chromatin accessibility enriched in proximal and distal gene regulatory states; in gene promoters, sex-biased chromatin accessibility was positively associated with sex-biased expression. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) also showed extensive sex-biased expression in the fiber-type and bulk data, respectively. Together, these results highlight nuclear and cytoplasmic mechanisms for sex-differential gene regulation in skeletal muscle
Polygenic risk score for type 2 diabetes shows context-dependent effects across populations
Get PDFPolygenic risk scores hold prognostic value for identifying individuals at higher risk of type 2 diabetes. However, further characterization is needed to understand the generalizability of type 2 diabetes polygenic risk scores in diverse populations across various contexts. We systematically characterize a multi-ancestry type 2 diabetes polygenic risk score among 244,637 cases and 637,891 controls across diverse populations from the Population Architecture Genomics and Epidemiology Study and 13 additional biobanks and cohorts. Polygenic risk score performance is context dependent, with better performance in those who are younger, male, without hypertension, and not obese or overweight. Additionally, the polygenic risk score is associated with various diabetes-related cardiometabolic traits and type 2 diabetes complications, suggesting its utility for stratifying risk of complications and identifying shared genetic architecture between type 2 diabetes and other diseases. These findings highlight the need to account for context when evaluating polygenic risk score as a tool for type 2 diabetes risk prognostication and the potentially generalizable associations of type 2 diabetes polygenic risk score with diabetes-related traits, despite differential performance in type 2 diabetes prediction across diverse populations. Our study provides a comprehensive resource to characterize a type 2 diabetes polygenic risk score
Roundabouts are for rich people: who gets traffic control devices and what to do about it
Get PDFAlmost every intersection has some form of traffic control. Stop signs and signals are ubiquitous, but recently roundabouts have become more common in the US. Roundabouts are generally safer than other intersection types, making their distribution an equity issue.
We motivate this research with qualitative work conducted in a working-class neighborhood in Durham, North Carolina, where community advocacy for roundabouts to improve safety has been unanswered by transportation officials. We expand this to the whole of North Carolina, modeling which intersections receive traffic signals, roundabouts, and other intersection designs. We find that impoverished and minority neighborhoods are more likely to have signalized intersections—largely a traffic flow intervention, rather than a safety one—while they are less likely to have roundabouts. We identify several partial explanations for this—notably that older neighborhoods, where less advantaged groups often live, have fewer roundabouts overall.
To address the issue, we propose an expanded process of Intersection Control Evaluation. This is a formalized process for evaluating the safety, traffic flow, community, and environmental impacts of traffic control devices. We propose that this be undertaken periodically for all intersections above a certain traffic volume, to ensure safety is adequately considered in all types of neighborhoods
THE LIBRARY COPYRIGHT INSTITUTE, 2019-2025: LESSONS LEARNED AND FUTURE DIRECTIONS FOR LIBRARY COPYRIGHT EDUCATION
Get PDFAlthough copyright has always been a component of librarianship, it has become essential over the last decade, as libraries and archives become increasingly digital. Library activities such as digitization, electronic reserves, and interlibrary loan all raise significant copyright issues. To address these issues, many well-resourced libraries employ lawyers or librarians with significant legal training to provide education and information about copyright and risk assessment for faculty, staff, and students, as well as internally within the library. Increasingly, even very small library or cultural heritage organizations with limited budgets need to make these kinds of assessments, often without the time and resources necessary to feel confident in their processes and conclusions.
NOTE: Siyao Cheng's portion of the white paper is a work in progress and will be updated in 2026
Enhancing Digital Health Literacy: Quality Assessment of Wellness and Nutrition Content on eHealthyinfo
Get PDFConsumer health informatics is becoming increasingly important in a world where more than 5 billion people rely on the internet and social media for health information. eHealthyinfo is a physician‐initiated and reviewed artificial intelligence (AI) applied digital health information website, aiming to be essential in advancing health literacy and promoting preventive health behaviors. To assess the effectiveness of its digital content, we conducted a mixed‐methods evaluation of 13 wellness and nutrition videos randomly selected from eHealthyinfo, representing 30% of its relevant content. Two independent reviewers used the Patient Education Materials Assessment Tool for Audiovisual Materials (PEMAT‐A/V) and the modified version of the CDC Clear Communication Index (CCI) to evaluate each video. Website log data were also analyzed to assess levels of user engagement. The average PEMAT scores were 89.5% for understandability and 100% for actionability, while the average CCI score was 94.4%, indicating the content was understandable, actionable, and clear. Weblog analysis revealed 16,000 active users, with an average engagement time of 41 seconds per user and a 27% average bounce rate for the examined year. eHealthyinfo demonstrates a strong potential as a digital health education tool, with high‐quality, user‐friendly content
SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade
Get PDFImmune checkpoint inhibitors (ICIs) extend survival in many patients with cancer but are ineffective in patients without pre-existing immunity1, 2, 3, 4, 5, 6, 7, 8–9. Although personalized mRNA cancer vaccines sensitize tumours to ICIs by directing immune attacks against preselected antigens, personalized vaccines are limited by complex and time-intensive manufacturing processes10, 11, 12, 13–14. Here we show that mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to ICIs. In preclinical models, SARS-CoV-2 mRNA vaccines led to a substantial increase in type I interferon, enabling innate immune cells to prime CD8+ T cells that target tumour-associated antigens. Concomitant ICI treatment is required for maximal efficacy in immunologically cold tumours, which respond by increasing PD-L1 expression. Similar correlates of vaccination response are found in humans, including increases in type I interferon, myeloid–lymphoid activation in healthy volunteers and PD-L1 expression on tumours. Moreover, receipt of SARS-CoV-2 mRNA vaccines within 100 days of initiating ICI is associated with significantly improved median and three-year overall survival in multiple large retrospective cohorts. This benefit is similar among patients with immunologically cold tumours. Together, these results demonstrate that clinically available mRNA vaccines targeting non-tumour-related antigens are potent immune modulators capable of sensitizing tumours to ICIs
Emergency care use in early pregnancy among North Carolina Medicaid beneficiaries
Get PDFObjective We sought to describe characteristics of pregnant Medicaid beneficiaries seeking emergency care in early pregnancy and to identify risk factors, specifically social drivers of health (SDOH), for emergency care use. Study design Linked Medicaid hospital claims, live birth records, and North Carolina Pregnancy Risk Screening Form data were used to identify risk factors for emergency care use among pregnancies resulting in a live birth between January 2014 and December 2019. Emergency care use included visits to the emergency department or obstetric triage unit that occurred in pregnancy prior to 20 weeks’ gestation. Demographic characteristics, SDOH, medical comorbidities, and pregnancy characteristics were assessed by the number of emergency care visits that occurred <20 weeks’ gestation. Multivariable ordered logistic regression modeled the association between potential SDOH risk factors for emergency care use and the number of emergency care visits (0, 1, 2, ≥3), adjusting for age, medical comorbidities, and pregnancy characteristics. Models were expressed as odds ratio (OR) with 95% confidence intervals (CI). Results A total of 70,669 (50.4%) pregnancies among North Carolina Medicaid beneficiaries had at least one emergency care visit prior to 20 weeks’ gestation; 36,327 (51.4%) had only 1 emergency care visit, 18,078 (25.6%) had 2 emergency care visits, and 16,264 (23.0%) had ≥3 emergency care visits. Compared to those with no emergency care use, those with any emergency care use prior to 20 weeks’ gestation more frequently identified as Black, were ≤35 years old, experienced physical violence or intimate partner violence within the past year, reported unstable living, food insecurity, and had a parent, friend, or partner with substance use disorder. In multivariable models, several SDOH were associated with increased odds of emergency care use before 20 weeks’ gestation, including having a high school education or less (OR, 1.23; 95% CI, 1.18–1.29), experience of physical violence within the last year (OR, 1.54; 95% CI, 1.45–1.64), food insecurity (OR, 1.20; 95% CI, 1.13–1.26), and housing instability (OR, 1.25; 95% CI, 1.17–1.34). Conclusion Half of pregnant Medicaid beneficiaries in North Carolina had ≥1 emergency care visit prior to 20 weeks’ gestation. Given the association between several SDOH and increased odds of emergency care use, early emergency care use in pregnancy may signal social and economic needs and opportunities for targeted intervention