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Supersaturation mutagenesis reveals adaptive rewiring of essential genes among malaria parasites
Get PDFINTRODUCTION:
Malaria parasites are highly divergent from model eukaryotes. Their distinctive biology means that many large-scale genome engineering methods that have been used effectively in model organisms, such as RNA interference or guide RNA–based CRISPR/Cas9 screening, are not applicable. As a result, there have been few systematic studies of gene function. The relatively poor level of functional annotation in Plasmodium genomes is a major barrier for the much-needed rational development of new antimalarial drugs and vaccines.
RATIONALE:
Plasmodium knowlesi is a zoonotic pathogen that is part of a large, understudied group of Plasmodium subgenus parasites that includes Plasmodium vivax, the dominant cause of malaria in South America and much of Asia. When cultured in human red blood cells, P. knowlesi has a rapid growth rate and high transfection efficiency, making it an ideal model system for large-scale experimental genetic studies. We used the piggyBac transposon mutagenesis system to generate high-density maps of gene essentiality in P. knowlesi parasites, providing the first large genetic screen in the Plasmodium subgenus representative of all other non-falciparum human-infecting species.
RESULTS:
We generated and mapped >175,000 transposon insertions in the P. knowlesi genome, which is substantially more than our previous ~38,000 insertion study of P. falciparum. This “supersaturation” level of mutagenesis, with an average transposon insertion frequency of every 138 base pairs, allowed us to score essentiality for 98% of genes. Further, the extraordinary density of mutations also allowed us to identify protected “void” regions within some genes, where insertions were not tolerated and which frequently contained predicted functional domains. This domain-level resolution of essentiality provides a completely new level of Plasmodium genome annotation.
CONCLUSION:
We compared our data with previously published genome-scale genetic studies of P. falciparum and the rodent malaria model Plasmodium berghei. Although the essentiality or redundancy of genes was conserved across all three species for the majority of genes for which data were available, a large number of genes are differentially essential, revealing species-specific adaptations. Our results indicate that Plasmodium essential gene evolution was conditionally linked to adaptive rewiring of metabolic networks for different hosts and their intracellular microenvironments, and that P. knowlesi in particular has a high level of metabolic plasticity that evidence suggests extends to other vivax-clade malaria parasites. These data provide new evolutionary insights into both distinct human-infective malaria parasite clades, which will inform multispecies target identification and intervention strategies
Long term health outcomes in people with diabetes 12 months after hospitalisation with COVID-19 in the UK: a prospective cohort study
Get PDFBackground: People with diabetes are at increased risk of hospitalisation, morbidity, and mortality following SARS-CoV-2 infection. Long-term outcomes for people with diabetes previously hospitalised with COVID-19 are, however, unknown. This study aimed to determine the longer-term physical and mental health effects of COVID-19 in people with and without diabetes. Methods: The PHOSP-COVID study is a multicentre, long-term follow-up study of adults discharged from hospital between 1 February 2020 and 31 March 2021 in the UK following COVID-19, involving detailed assessment at 5 and 12 months after discharge. The association between diabetes status and outcomes were explored using multivariable linear and logistic regressions. Findings: People with diabetes who survived hospital admission with COVID-19 display worse physical outcomes compared to those without diabetes at 5- and 12-month follow-up. People with diabetes displayed higher fatigue (only at 5 months), frailty, lower physical performance, and health-related quality of life and poorer cognitive function. Differences in outcomes between diabetes status groups were largely consistent from 5 to 12-months. In regression models, differences at 5 and 12 months were attenuated after adjustment for BMI and presence of other long-term conditions. Interpretation: People with diabetes reported worse physical outcomes up to 12 months after hospital discharge with COVID-19 compared to those without diabetes. These data support the need to reduce inequalities in long-term physical and mental health effects of SARS-CoV-2 infection in people with diabetes
Global investment and cultural traditions
No full textProfessional football in Europe is a highly commercialized and mediatized sport, which through television and social media networks has become both a media ‘product’ and part of a global entertainment industry. Conversely, football and football fandom have deep cultural roots in communities and families, which provide important social networks built on cultural traditions, values and practices often placed in conflict with, and at risk by, global commercial interests. This chapter aims to investigate the social and ethical questions raised by the changing nature of professional football club ownership and commercial interests on the long-established cultural heritage of such clubs, their supporters and values. It also seeks to set out an agenda for future research in this area of growing political and economic importance
Solving a paradox: can learning about climate change and sustainable healthcare be fun?
Get PDFClimate change and education for sustainable healthcare are important and essential topics to address in higher education, but which have the potential to be anxiety-inducing. In our medical school, we have used a ludic pedagogy with a solutions-based framework to deliver a student selected component addressing sustainable healthcare and climate
change. This involved the use of serious games, flipped classroom model, formative ungraded presentations, interprofessional learning, experiential learning and community links, summative engagement, and the creation of individual action plans in an aim to deliver transformative learning. In this case study, we will outline the various techniques used for this approach; our reflections on the effectiveness, benefits, and limitations; and finish with recommendations for educators and suggestions for further research and pedagogical developments to support joyful transformative learning of potentially anxiety-inducing topics
Roadmap for alleviating the manifestations of ageing in the cardiovascular system
Get PDFAgeing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulatory system not only supplies nutrients and oxygen to all tissues of the human body and removes by-products but also builds the largest interorgan communication network, thereby serving as a gatekeeper for healthy ageing. Therefore, elucidating organ-specific and cell-specific ageing mechanisms that compromise circulatory system functions could have the potential to prevent or ameliorate age-related cardiovascular diseases. In support of this concept, emerging evidence suggests that targeting the circulatory system might restore organ function. In this Roadmap, we delve into the organ-specific and cell-specific mechanisms that underlie ageing-related changes in the cardiovascular system. We raise unanswered questions regarding the optimal design of clinical trials, in which markers of biological ageing in humans could be assessed. We provide guidance for the development of gerotherapeutics, which will rely on the technological progress of the diagnostic toolbox to measure residual risk in elderly individuals. A major challenge in the quest to discover interventions that delay age-related conditions in humans is to identify molecular switches that can delay the onset of ageing changes. To overcome this roadblock, future clinical trials need to provide evidence that gerotherapeutics directly affect one or several hallmarks of ageing in such a manner as to delay, prevent, alleviate or treat age-associated dysfunction and diseases
From parasocial interaction to parasocial relationship: a review and research agenda
No full textParasocial interaction (PSI) and parasocial relationship (PSR) are important and widespread phenomena in both offline and online marketing. While extensive, prior work on PSI and PSR is riddled with inconsistencies and needs an updated perspective. First, research needs to establish whether and why PSI and PSR represent different concepts with unique characteristics. Furthermore, the conceptualization of PSI and PSR remains predominantly rooted in offline contexts, despite the shift in media consumption toward online platforms. By systematically reviewing 233 peer-reviewed journal articles published between 1956 and 2023, this study provides a nuanced perspective on the evolution of PSI and PSR in offline and online environments. Theoretically, it contributes to the literature by proposing seven key criteria to differentiate PSI from PSR in offline and online contexts, as well as offering new conceptualizations of PSI and PSR in the online environment. Using the Theories–Characteristics–Contexts–Methods (TCCM) framework, this work presents a comprehensive overview of the current state of research and discusses future research directions
Exercise-based cardiac rehabilitation for patients with atrial fibrillation: a narrative review
Get PDFThe role of physical activity (i.e. any bodily movement that requires energy expenditure) and exercise (i.e. planned, structured, and repetitive physical activity to improve/maintain fitness) in the primary and secondary prevention of atrial fibrillation (AF) is increasingly recognized. Physical activity has been associated with lower risks to develop AF and associated complications (e.g. stroke, heart failure, and myocardial infarction). Exercise-based cardiac rehabilitation (ExCR) is increasingly examined in the treatment of AF and sometimes combined with rhythm control strategies (e.g. catheter ablation). Nonetheless, several important clinical, practical, and mechanistic questions remain not fully understood. This state-of-the-art review first provides a contemporary update on the evidence base for the clinical effects of ExCR in AF. Despite the ongoing need for high-quality studies, existing randomized controlled trials and cohort studies suggest ExCR reduces AF burden, lowers risks for major adverse cardiovascular events, and improves health-related quality of life. Second, to facilitate implementation of ExCR, we have observed comparable effects of distinct exercise protocols (e.g. type of training and centre-/home-based) and discussed similarity of effectiveness across patient characteristics (e.g. age, sex, and AF subtype). Critically, we have discussed potential barriers that may prohibit the uptake of ExCR for patients with AF, categorized at clinician- (e.g. referral and training), patient- (e.g. motivation, transportation, and psychosocial factors), and system-levels (e.g. insurance and resources). Third, we have summarized the potential mechanisms underlying these effects of ExCR, classified by their potential role in reducing AF burden (e.g. atrial/ventricular function, autonomic balance, and inflammation) and lowering risks for adverse events (e.g. modifiable risk factors, vascular function, and thrombogenesis). Based on the increasing evidence for clinical benefits, e.g. improved health-related quality of life and better clinical outcomes, we advocate stronger focus on regular physical activity and referral to multidisciplinary ExCR for sustainable lifestyle changes within the ESC AF-CARE pathway for the prevention and treatment of AF
The influence between frailty, sarcopenia and physical status on mortality in patients undergoing emergency laparotomy
Get PDFBackground:
Frailty and sarcopenia have been independently shown to predict mortality in emergency laparotomy (EmLap), and both can be indicative of poor physical status. We aim to assess the prevalence of frailty, sarcopenia, and physical status in EmLap and explore the relationship between these factors and 30-day, 90-day and 1-year mortality.
Methods:
Retrospective analysis was performed on prospectively maintained Emergency Laparotomy and Laparoscopic Scottish Audit (ELLSA) database (2017–2019) which included patients ≥ 18 years who underwent EmLap. Clinical frailty scale (CFS) was used to classify frailty (score ≥ 4 as frail). Sarcopenia was assessed using total psoas index (TPI). Poor physical status (PPS) was defined by American Society of Anaesthesiologists physical status classification (ASA) ≥ 4. Binary logistic regression and fisher’s exact tests were used for statistical analysis.
Results:
215 patients were included in the study, with 57.2% female and median age of 64 years. Frailty was present in 17.2%, sarcopenia in 25.1% and 14.4% had PPS; 3.3% had all three factors. Frail patients had significantly higher risk for 30-day (p = 0.003), 90-day (p = 0.006) and 1-year mortality (p = 0.032). Patients with poor physical status also showed significantly higher mortality at 30-day (p < 0.001), 90-day (p < 0.001) and 1-year (p = 0.001). Sarcopenic patients did not show significant differences in mortality risks up to 1 year. Patients with all three factors had significantly higher 30-day (p = 0.003), 90-day (p = 0.046) and 1-year mortality (p = 0.108) compared to patients who had none of the factors.
Conclusions:
Frailty, sarcopenia, and PPS are prevalent in EmLap. Frailty and PPS were independently associated with short and long-term mortality, but not sarcopenia. While overlap exists between three factors, more research is required to understand the complex interplay
Dual graph‐based Bayesian network modeling with Rao‐Blackwellization for seismic reliability and complexity quantification of network connectivity
Get PDFModern societies depend on various lifeline networks such as transportation, electricity, and gas distribution systems, which are vulnerable to seismic events. Although numerous analytical and simulation‐based methods have been developed for efficient seismic system reliability analysis (SRA), dealing with high‐dimensional events arising from large‐scale infrastructure networks remains challenging. To address this challenge, this paper proposes a system reliability method that efficiently computes the connectivity of directed graphs. The method employs the dual graph representation of a target system to automate the construction of a Bayesian network (BN). This enables the application of the junction tree algorithm, a well‐established BN inference method, to perform reliability analysis and quantify complexity based on a network topology. The paper further tackles SRA challenges associated with fully correlated seismic uncertainties, which typically lead to a significant increase in computational complexity. To this end, we propose to combine a cross entropy‐based adaptive importance sampling technique with Rao‐Blackwellization. Thereby, sampling methods and exact analytical inference can be effectively combined to improve computational efficiency for seismic SRA of lifeline networks. The proposed methods are demonstrated through three numerical examples
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