Low-altitude signatures of the cusp and flux transfer events

The usual interpretation of a flux transfer event (FTE) at the magnetopause, in terms of time-dependent and possibly patchy reconnection, demands that it generate an ionospheric signature. Recent ground-based observations have revealed that auroral transients in the cusp/cleft region have all the characteristics required of FTE effects. However, signatures in the major available dataset, namely that from low-altitude polar-orbiting satellites, have not yet been identified. In this paper, we consider a cusp pass of the DE-2 spacecraft during strongly southward IMF. The particle detectors show magnetosheath ion injection signatures. However, the satellite motion and convection are opposed, and we discuss how the observed falling energy dispersion of the precipitating ions can have arisen from a static, moving or growing source. The spatial scale of the source is typical of an FTE. A simple model of the ionospheric signature of an FTE reproduces the observed electric and magnetic field perturbations. Precipitating electrons of peak energy ∼100eV are found to lie on the predicted boundary of the newly-opened tube, very similar to those found on the edges of FTEs at the magnetopause. The injected ions are within this boundary and their dispersion is consistent with its growth as reconnection proceeds. The reconnection potential and the potential of the induced ionospheric motion are found to be the same (≃25kV). The scanning imager on DE-1 shows a localised transient auroral feature around DE-2 at this time, similar to the recent optical/radar observations of FTEs

Adolescents' experiences of the therapeutic effects of sport participation

This research study is a qualitative research study which examines the experiences of adolescents in Soshanguve who are participating in sport. The aim of the study is to explore the value of sport participation as a therapeutic tool. The problem statement is how adolescents experience the effects of sport participation. The research study was conducted using ethnomethodology which examines how people make sense of their daily lives. The intention was to focus on how the participants interpreted their everyday activities. The absence of symptoms that one would expect from the participants was viewed as an indicator of therapeutic effects of sport participation. There appeared to be an absence of depressive and anxious symptoms, no substance use and sound academic results. Participants also displayed a generally positive outlook on their futures. The conclusion was that sport participation has some benefits for adolescents.PsychologyM.A. (Clinical Psychology

Impaired natural killer cell phenotype and function in idiopathic and heritable pulmonary arterial hypertension

BACKGROUND: Beyond their role as innate immune effectors, natural killer (NK) cells are emerging as important regulators of angiogenesis and vascular remodeling. Pulmonary arterial hypertension (PAH) is characterized by severe pulmonary vascular remodeling and has long been associated with immune dysfunction. Despite this association, a role for NK cells in disease pathology has not yet been described. METHODS AND RESULTS: Analysis of whole blood lymphocytes and isolated NK cells from PAH patients revealed an expansion of the functionally defective CD56(-)/CD16(+) NK subset that was not observed in patients with chronic thromboembolic pulmonary hypertension. NK cells from PAH patients also displayed decreased levels of the activating receptor NKp46 and the killer immunoglobulin-like receptors 2DL1/S1 and 3DL1, reduced secretion of the cytokine macrophage inflammatory protein-1β, and a significant impairment in cytolytic function associated with decreased killer immunoglobulin-like receptor 3DL1 expression. Genotyping patients (n=222) and controls (n=191) for killer immunoglobulin-like receptor gene polymorphisms did not explain these observations. Rather, we show that NK cells from PAH patients exhibit increased responsiveness to transforming growth factor-β, which specifically downregulates disease-associated killer immunoglobulin-like receptors. NK cell number and cytotoxicity were similarly decreased in the monocrotaline rat and chronic hypoxia mouse models of PAH, accompanied by reduced production of interferon-γ in NK cells from hypoxic mice. NK cells from PAH patients also produced elevated quantities of matrix metalloproteinase 9, consistent with a capacity to influence vascular remodeling. CONCLUSIONS: Our work is the first to identify an impairment of NK cells in PAH and suggests a novel and substantive role for innate immunity in the pathobiology of this disease

Extracorporeal membrane oxygenation and Extracorporeal Membrane Oxygenation Cardiopulmonary Resusciation (ECPR) research priorities in Australia: a clinician survey

Background The use of extracorporeal membrane oxygenation (ECMO) for cardiorespiratory failure and during cardiopulmonary resuscitation has increased significantly and is resource intensive. High-quality evidence to guide management of patients on ECMO is limited. Objectives The objective of this study was to determine the research priorities of clinicians for ECMO and Extracorporeal Membrane Oxygenation Cardiopulmonary Resusciation (ECPR) in Australia and New Zealand. Methods A prospective, binational survey of clinicians was conducted in May 2022. Results There were 133 respondents; 110 (84%) worked at an Australian ECMO centre; 28 (21%) were emergency, 45 (34%) were intensive care, and 41 (31%) were nursing clinicians. All aspects of ECMO care were identified by respondents as being important for further research; however, appropriate patient selection and determining long-term outcomes were ranked the highest. While most believed ECMO was efficacious, they felt that there was insufficient evidence to determine cost-effectiveness. There was uncertainty of the best model of ECPR provision. Equipoise exists for randomised studies into anticoagulation, blood product usage, and ECPR. Conclusions This survey found strong support amongst clinicians for further research into the optimal use of ECMO and ECPR and provides a frame work for prioritising future clinical trials and research agendas

Predicting population coverage of T-cell epitope-based diagnostics and vaccines

BACKGROUND: T cells recognize a complex between a specific major histocompatibility complex (MHC) molecule and a particular pathogen-derived epitope. A given epitope will elicit a response only in individuals that express an MHC molecule capable of binding that particular epitope. MHC molecules are extremely polymorphic and over a thousand different human MHC (HLA) alleles are known. A disproportionate amount of MHC polymorphism occurs in positions constituting the peptide-binding region, and as a result, MHC molecules exhibit a widely varying binding specificity. In the design of peptide-based vaccines and diagnostics, the issue of population coverage in relation to MHC polymorphism is further complicated by the fact that different HLA types are expressed at dramatically different frequencies in different ethnicities. Thus, without careful consideration, a vaccine or diagnostic with ethnically biased population coverage could result. RESULTS: To address this issue, an algorithm was developed to calculate, on the basis of HLA genotypic frequencies, the fraction of individuals expected to respond to a given epitope set, diagnostic or vaccine. The population coverage estimates are based on MHC binding and/or T cell restriction data, although the tool can be utilized in a more general fashion. The algorithm was implemented as a web-application available at . CONCLUSION: We have developed a web-based tool to predict population coverage of T-cell epitope-based diagnostics and vaccines based on MHC binding and/or T cell restriction data. Accordingly, epitope-based vaccines or diagnostics can be designed to maximize population coverage, while minimizing complexity (that is, the number of different epitopes included in the diagnostic or vaccine), and also minimizing the variability of coverage obtained or projected in different ethnic groups

Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant hypoxia-inducible factor (HIF)2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades. Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed, followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from idiopathic PAH patients were used to determine the impact of HIF2α-inhibition on endothelial function. Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH-associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline-exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage. In vitro, loss of HIF2α signalling in human pulmonary arterial endothelial cells suppresses target genes associated with inflammation, and PT2567 reduced the hyperproliferative phenotype and overactive arginase activity in blood outgrowth endothelial cells from idiopathic PAH patients. These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population

An association between the acute phase response and patterns of antigen induced T cell proliferation in juvenile idiopathic arthritis

The aim of this research was to determine whether all memory T cells have the same propensity to migrate to the joint in patients with juvenile idiopathic arthritis. Paired synovial fluid and peripheral blood mononuclear cell proliferative responses to a panel of antigens were measured and the results correlated with a detailed set of laboratory and clinical data from 39 patients with juvenile idiopathic arthritis. Two distinct patterns of proliferative response were found in the majority of patients: a diverse pattern, in which synovial fluid responses were greater than peripheral blood responses for all antigens tested; and a restricted pattern, in which peripheral blood responses to some antigens were more vigorous than those in the synovial fluid compartment. The diverse pattern was generally found in patients with a high acute phase response, whereas patients without elevated acute phase proteins were more likely to demonstrate a restricted pattern. We propose that an association between the synovial fluid T cell repertoire and the acute phase response suggests that proinflammatory cytokines may influence recruitment of memory T cells to an inflammatory site, independent of their antigen specificity. Additionally, increased responses to enteric bacteria and the presence of αEβ7 T cells in synovial fluid may reflect accumulation of gut associated T cells in the synovial compartment, even in the absence of an elevated acute phase response. This is the first report of an association between the acute phase response and the T cell population recruited to an inflammatory site

Bone morphogenetic protein signaling is required for RAD51-mediated maintenance of genome integrity in vascular endothelial cells.

The integrity of blood vessels is fundamental to vascular homeostasis. Inactivating mutations in the bone morphogenetic protein (BMP) receptor type II (BMPR2) gene cause hereditary vascular disorders, including pulmonary arterial hypertension and hereditary hemorrhagic telangiectasia, suggesting that BMPR2 and its downstream signaling pathway are pivotal to the maintenance of vascular integrity through an unknown molecular mechanism. Here we report that inactivation of BMPR2 in pulmonary vascular endothelial cells results in a deficit of RAD51, an enzyme essential for DNA repair and replication. Loss of RAD51, which causes DNA damage and cell death, is also detected in animal models and human patients with pulmonary arterial hypertension. Restoration of BMPR2 or activation of the BMP signaling pathway rescues RAD51 and prevents DNA damage. This is an unexpected role of BMP signaling in preventing the accumulation of DNA damage and the concomitant loss of endothelial integrity and vascular remodeling associated with vascular disorders

Targeting translational read-through of premature termination mutations in BMPR2 with PTC124 for pulmonary arterial hypertension

Pulmonary arterial hypertension is a fatal disorder of the lung circulation in which accumulation of vascular cells progressively obliterates the pulmonary arterioles. This results in sustained elevation in pulmonary artery pressure leading eventually to right heart failure. Approximately, 80% of familial and 20% of sporadic idiopathic pulmonary arterial hypertension cases are caused by mutations in the bone morphogenetic protein receptor type 2 (BMPR2). Nonsense mutations in BMPR2 are amongst the most common mutations found, where the insertion of a premature termination codon causes mRNA degradation via activation of the nonsense-mediated decay pathway leading to a state of haploinsufficiency. Ataluren (PTC124), a compound that permits ribosomal read-through of premature stop codons, has been previously reported to increase BMPR2 protein expression in cells derived from pulmonary arterial hypertension patients harbouring nonsense mutations. In this study, we characterised the effects of PTC124 on a range of nonsense BMPR2 mutations, focusing on the R584X mutation both in vitro and in vivo. Treatment with PTC124 partially restored BMPR2 protein expression in blood outgrowth endothelial cells isolated from a patient harbouring the R584X mutation. Furthermore, a downstream bone morphogenetic protein signalling target, Id1, was rescued by PTC124 treatment. Mutant cells also exhibited increased lipopolysaccharide-induced permeability, which was reversed by PTC124 treatment. Increased proliferation and apoptosis in R584X blood outgrowth endothelial cells were also significantly reduced by PTC124. Moreover, oral PTC124 increased lung BMPR2 protein expression in mice harbouring the R584X mutation (Bmpr2+/R584X). Our findings provide support for future experimental medicine studies of PTC124 in pulmonary arterial hypertension patients with specific nonsense BMPR2 mutations

Transcript analysis reveals a specific HOX signature associated with positional identity of human endothelial cells.

The endothelial cell has a remarkable ability for sub-specialisation, adapted to the needs of a variety of vascular beds. The role of developmental programming versus the tissue contextual environment for this specialization is not well understood. Here we describe a hierarchy of expression of HOX genes associated with endothelial cell origin and location. In initial microarray studies, differential gene expression was examined in two endothelial cell lines: blood derived outgrowth endothelial cells (BOECs) and pulmonary artery endothelial cells. This suggested shared and differential patterns of HOX gene expression between the two endothelial lines. For example, this included a cluster on chromosome 2 of HOXD1, HOXD3, HOXD4, HOXD8 and HOXD9 that was expressed at a higher level in BOECs. Quantative PCR confirmed the higher expression of these HOXs in BOECs, a pattern that was shared by a variety of microvascular endothelial cell lines. Subsequently, we analysed publically available microarrays from a variety of adult cell and tissue types using the whole "HOX transcriptome" of all 39 HOX genes. Using hierarchical clustering analysis the HOX transcriptome was able to discriminate endothelial cells from 61 diverse human cell lines of various origins. In a separate publically available microarray dataset of 53 human endothelial cell lines, the HOX transcriptome additionally organized endothelial cells related to their organ or tissue of origin. Human tissue staining for HOXD8 and HOXD9 confirmed endothelial expression and also supported increased microvascular expression of these HOXs. Together these observations suggest a significant involvement of HOX genes in endothelial cell positional identity