Optimising Antibiotic Usage to Treat Bacterial Infections

The increase in antibiotic resistant bacteria poses a threat to the continued use of antibiotics to treat bacterial infections. The overuse and misuse of antibiotics has been identified as a significant driver in the emergence of resistance. Finding optimal treatment regimens is therefore critical in ensuring the prolonged effectiveness of these antibiotics. This study uses mathematical modelling to analyse the effect traditional treatment regimens have on the dynamics of a bacterial infection. Using a novel approach, a genetic algorithm, the study then identifies improved treatment regimens. Using a single antibiotic the genetic algorithm identifies regimens which minimise the amount of antibiotic used while maximising bacterial eradication. Although exact treatments are highly dependent on parameter values and initial bacterial load, a significant common trend is identified throughout the results. A treatment regimen consisting of a high initial dose followed by an extended tapering of doses is found to optimise the use of antibiotics. This consistently improves the success of eradicating infections, uses less antibiotic than traditional regimens and reduces the time to eradication. The use of genetic algorithms to optimise treatment regimens enables an extensive search of possible regimens, with previous regimens directing the search into regions of better performance

TAKE-OFF FORCES AND IMPULSES IN THE LONG JUMP

A series of jumps by an experienced female athlete were recorded with a force platform and a high-speed video camera. We obtained a wide range of run-up velocities by using direct intervention to set the length of the athlete’s run-up. In all jumps the horizontal take-off force was predominantly a backwards braking force and so the athlete’s horizontal velocity was substantially reduced during the take-off. The athlete’s breaking impulse increased with increasing run-up velocity, but not so much as to negate the increase in run-up velocity. The optimum long jump take-off technique is a compromise between the conflicting desires of generating vertical impulse and minimising the horizontal braking impulse. We currently have no firm recommendation as to the usefulness of a force platform in improving an athlete’s take-off technique

Emergent Error Correcting States in Networks of Nonlinear Oscillators

Networks of nonlinear oscillators can exhibit complex collective behaviour ranging from synchronised states to chaos. Here, we simulate the dynamics of three coupled Duffing oscillators whose multiple equilibrium states can be used for information processing and storage. Our analysis reveals that even for this small network, there is the emergence of an error correcting phase where the system autonomously corrects errors from random impulses. The system has several surprising and attractive features, including dynamic isolation of resonators exposed to extreme impulses and the ability to correct simultaneous errors. The existence of an error correcting phase opens the prospect of fault-tolerant information storage, with particular applications in nanomechanical computing

MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension

Rationale: The pathogenesis of PAH remains unclear. The four microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered. Objective: To elucidate the transcriptional regulation of the miR-143/145 cluster, and the role of miR-143 in PAH. Methods and Results: We identified the promoter region that regulates miR-143/145 miRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signalling pathways, including estrogens receptor (ER), liver X factor/retinoic X receptor (LXR/RXR), TGF-β (Smads), and hypoxia (HRE) that regulated levels of all pri-miR stem loop transcription and resulting miRNA expression. We observed that miR-143-3p is selectively upregulated compared to miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMCs-derived exosomes. Using assays with pulmonary arterial endothelial cells (PAECs) we demonstrated a paracrine pro-migratory and pro-angiogenic effect of miR-143-3p enriched exosomes from PASMC. Quantitative PCR and in situ hybridisation showed elevated expression of miR-143 in calf models of PAH as well as in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role for miR-143 in experimental PH in vivo in miR-143-/- and antimiR143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings. Conclusions: MiR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, while inhibition of miR-143-3p blocked experimental PH. Taken together these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology

Animal displacement from marine energy development : Mechanisms and consequences

This work would not be possible without funding support from the U.S. Department of Energy, Energy Efficiency and Renewable Energy Water Power Technologies Office to Pacific Northwest National Laboratory (PNNL) under contract DE-AC05- 76RL01830 . We are grateful to all the international marine energy researchers and regulatory advisors who attended the online Expert Forum hosted by OES-Environmental on December 7th, 2022, and provided feedback and input on an earlier version of this work. We also thank Stephanie King (PNNL) for creating the original illustrations, as well as the anonymous reviewers for their constructive feedback.For marine wave and tidal energy to successfully contribute to global renewable energy goals and climate change mitigation, marine energy projects need to expand beyond small deployments to large-scale arrays. However, with large-scale projects come potential environmental effects not observed at the scales of single devices and small arrays. One of these effects is the risk of displacing marine animals from their preferred habitats or their migration routes, which may increase with the size of arrays and location. Many marine animals may be susceptible to some level of displacement once large marine energy arrays are increasingly integrated into the seascape, including large migratory animals, non-migratory pelagic animals with large home ranges, and benthic and demersal mobile organisms with more limited ranges, among many others. Yet, research around the mechanisms and effects of displacement have been hindered by the lack of clarity within the international marine energy community regarding the definition of displacement, how it occurs, its consequences, species of concern, and methods to investigate the outcomes. This review paper leveraged lessons learned from other industries, such as offshore development, to establish a definition of displacement in the marine energy context, explore which functional groups of marine animals may be affected and in what way, and identify pathways for investigating displacement through modeling and monitoring. In the marine energy context, we defined displacement as the outcome of one of three mechanisms (i.e., attraction, avoidance, and exclusion) triggered by an animal's response to one or more stressors acting as a disturbance, with various consequences at the individual through population levels. The knowledge gaps highlighted in this study will help the regulatory and scientific communities prepare for mitigating, observing, measuring, and characterizing displacement of various animals around marine energy arrays in order to prevent irreversible consequences.Peer reviewe

Six weeks of conditioning exercise increases total, but not free testosterone in lifelong sedentary aging men

Introduction: Advancing age is associated with a gradual decline in circulating androgens, and the putative role of exercise training on systemic androgens remains to be adequately defined. Methods: The present investigation examined the impact of 6 weeks of supervised exercise training on resting levels of systemic hormones in a cohort of lifelong sedentary men [SED (n = 28), 62.5 ± 5.3 years], compared with a positive control group of age-matched lifelong exercisers [LE (n = 20), 60.4 ± 4.7 years, >30 years training history]. Blood hormones were sampled pre- and post-intervention from an antecubital forearm vein and analysed using electrochemiluminescent immunoassay. Cardiorespiratory fitness () was determined via indirect calorimetry during an incremental cycle test to volitional exhaustion. Results: Analysis of variance (ANOVA) revealed a lack of significant change in any parameter amongst LE, whilst SED experienced a significant exercise-induced improvement in cardiorespiratory fitness and total testosterone (all p  0.05) amongst SED. Conclusions: Although resting levels of systemic total testosterone increased in response to 6 weeks of exercise training, increases in SHBG negated any potential relationship between calculated-free or bioavailable testosterone. These findings indicate that increases in bioavailable testosterone fraction are not required for cardiorespiratory fitness improvements in aging men

Conceptual Underpinnings for Transformative Research in a Service Ecosystems Context to Resolve Social Issues – Framework Foundations and Extensions

A number of services within society are designed to improve the well-being of its members and transform lives. Some services focus on the protection and support of vulnerable members of society, for example, those suffering the effects of drug use, mental health conditions, violence or poverty. Clients of such social services may also come from minority or marginalised cultural backgrounds. Typically, social services aim to reduce disparities and enhance individual and population well-being. A major challenge for social policy-makers and social service providers is to establish and maintain constructive engagement between the social services and those they are intended to serve. Some of these vulnerable clients are deemed ‘hard-to-reach’ (HTR) by policy-makers and service providers. Yet, the transformation of lives requires the involvement of the focal actor (client) and their service or activity system, as well as the engagement of other actors, such as the social worker embedded in their service or activity system. This paper aims to further unpack a novel approach, called integrative transformative service framework. This contribution extends its conceptualisation which fuses mainly three different approaches, namely Transformative Service Research (TSR), (Cultural-Historical) Activity Theory (CHAT) and (Regulatory) Engagement Theory (RET)

Using plant volatile traps to develop phenology models for natural enemies: An example using Chrysopa nigricornis (Burmeister) (Neuroptera: Chrysopidae)

A model predicting phenology of adult Chrysopa nigricornis (Burmeister) (Neuroptera: Chrysopidae) in orchards was developed from field (trapping) data supplemented with development data collected under laboratory conditions. Lower and upper thresholds of 10.1°C and 29.9°C, respectively, were estimated from published and unpublished laboratory observations, and were used to develop a phenology model. Season-long field data were collected using white delta traps that had been baited with squalene, a volatile shown previously to be highly attractive to C. nigricornis. The model was developed from data collected in three Washington apple orchards, and was validated using independent data sets collected from apple, sweet cherry, pear, and walnut orchards over a 2–4year period across a much wider geographic region. We found that the mean absolute deviation across all crops and years was 39.7±1.2day-degrees (DD), or 4.4±0.14days. Populations of C. nigricornis from walnut orchards in California emerged 105DD later than those in Oregon and Washington, thus requiring correction of average time of first trap catch in California to synchronize models. The ability to use a single model across multiple crops, different prey species and abundances, and different pesticide regimes demonstrates that phenology models for generalist predators may have broader application to IPM programs in other cropping systems

Searching for Sharp Drops in the Incidence of Pandemic A/H1N1 Influenza by Single Year of Age

BACKGROUND During the 2009 H1N1 pandemic (pH1N1), morbidity and mortality sparing was observed among the elderly population; it was hypothesized that this age group benefited from immunity to pH1N1 due to cross-reactive antibodies generated from prior infection with antigenically similar influenza viruses. Evidence from serologic studies and genetic similarities between pH1N1 and historical influenza viruses suggest that the incidence of pH1N1 cases should drop markedly in age cohorts born prior to the disappearance of H1N1 in 1957, namely those at least 52-53 years old in 2009, but the precise range of ages affected has not been delineated. METHODS AND FINDINGS To test for any age-associated discontinuities in pH1N1 incidence, we aggregated laboratory-confirmed pH1N1 case data from 8 jurisdictions in 7 countries, stratified by single year of age, sex (when available), and hospitalization status. Using single year of age population denominators, we generated smoothed curves of the weighted risk ratio of pH1N1 incidence, and looked for sharp drops at varying age bandwidths, defined as a significantly negative second derivative. Analyses stratified by hospitalization status and sex were used to test alternative explanations for observed discontinuities. We found that the risk of laboratory-confirmed infection with pH1N1 declines with age, but that there was a statistically significant leveling off or increase in risk from about 45 to 50 years of age, after which a sharp drop in risk occurs until the late fifties. This trend was more pronounced in hospitalized cases and in women and was independent of the choice in smoothing parameters. The age range at which the decline in risk accelerates corresponds to the cohort born between 1951-1959 (hospitalized) and 1953-1960 (not hospitalized). CONCLUSIONS The reduced incidence of pH1N1 disease in older individuals shows a detailed age-specific pattern consistent with protection conferred by exposure to influenza A/H1N1 viruses circulating before 1957.The project described was supported by the National Institute Of General Medical Sciences [Award Number U54GM088558], http://www.nigms.nih. gov/. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute Of General Medical Sciences or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript