HIV-Derived ssRNA Binds to TLR8 to Induce Inflammation-Driven Macrophage Foam Cell Formation

Even though combined anti-retroviral therapy (cART) dramatically improves patient survival, they remain at a higher risk of being afflicted with non-infectious complications such as cardiovascular disease (CVD). This increased risk is linked to persistent inflammation and chronic immune activation. In this study, we assessed whether this complication is related to HIV-derived ssRNAs inducing in macrophages increases in TNFα release through TLR8 activation leading to foam cell formation. HIV ssRNAs induced foam cell formation in monocyte-derived macrophages (MDMs) in a dose-dependent manner. This response was reduced when either endocytosis or endosomal acidification was inhibited by dynasore or chloroquine, respectively. Using a flow cytometry FRET assay, we demonstrated that ssRNAs bind to TLR8 in HEK cells. In MDMs, ssRNAs triggered a TLR8-mediated inflammatory response that ultimately lead to foam cell formation. Targeted silencing of the TLR8 and MYD88 genes reduced foam cell formation. Furthermore, foam cell formation induced by these ssRNAs was blocked by an anti-TNFα neutralizing antibody. Taken together in MDMs, HIV ssRNAs are internalized; bind TLR8 in the endosome followed by endosomal acidification. TLR8 signaling then triggers TNFα release and ultimately leads to foam cell formation. As this response was inhibited by a blocking anti-TNFα antibody, drug targeting HIV ssRNA-driven TLR8 activation may serve as a potential therapeutic target to reduce chronic immune activation and inflammation leading to CVD in HIV+ patients

Factors Affecting Definitions of and Approaches to Integrative Medicine: A Mixed Methods Study Examining China’s Integrative Medicine Development

Aim. This study identifies existing definitions and approaches among China’s integrative medicine (IM) experts and examines relationships with key characteristics distinguishing individual experts. Methods. Snowball sampling was used to select 73 IM experts for semistructured interviews. In this mixed methods study, we first identified definitions and approaches through analyzing core statements. Four key factors, including age, education, practice type, and working environment, were then chosen to evaluate the associations with the definitions. Results. Four unique definitions were identified, including IM as a “new medicine” (D1), as a combination of western medicine (WM) and Chinese medicine (CM) (D2), as a modernization of CM (D3), and as a westernization of CM (D4). D4 was mostly supported by those working in WM organizations, while D3 was more prominent from individuals working in CM organizations (P=0.00004). More than 64% clinicians had D2 while only 1 (5.9%) nonclinician had D2. Only 1 clinician (1.8%) had D4 while almost 30% nonclinicians had D4 (P=0.0001). Among nonclinicians working in WM organizations, 83.3% of them had D4 (P=0.001). Conclusion. Findings indicate that institutional structure and practice type are factors affecting IM approaches. These results carry implications for the ways in which western countries move forward with the definition and implementation of IM

Climate–ecosystem modelling made easy: The Land Sites Platform

Dynamic Global Vegetation Models (DGVMs) provide a state-of-the-art process-based approach to study the complex interplay between vegetation and its physical environment. For example, they help to predict how terrestrial plants interact with climate, soils, disturbance and competition for resources. We argue that there is untapped potential for the use of DGVMs in ecological and ecophysiological research. One fundamental barrier to realize this potential is that many researchers with relevant expertize (ecology, plant physiology, soil science, etc.) lack access to the technical resources or awareness of the research potential of DGVMs. Here we present the Land Sites Platform (LSP): new software that facilitates single-site simulations with the Functionally Assembled Terrestrial Ecosystem Simulator, an advanced DGVM coupled with the Community Land Model. The LSP includes a Graphical User Interface and an Application Programming Interface, which improve the user experience and lower the technical thresholds for installing these model architectures and setting up model experiments. The software is distributed via version-controlled containers; researchers and students can run simulations directly on their personal computers or servers, with relatively low hardware requirements, and on different operating systems. Version 1.0 of the LSP supports site-level simulations. We provide input data for 20 established geo-ecological observation sites in Norway and workflows to add generic sites from public global datasets. The LSP makes standard model experiments with default data easily achievable (e.g., for educational or introductory purposes) while retaining flexibility for more advanced scientific uses. We further provide tools to visualize the model input and output, including simple examples to relate predictions to local observations. The LSP improves access to land surface and DGVM modelling as a building block of community cyberinfrastructure that may inspire new avenues for mechanistic ecosystem research across disciplines.publishedVersio

Mental health first aid training for nursing students: a protocol for a pragmatic randomised controlled trial in a large university

BackgroundThe impact of mental health problems and disorders in Australia is significant. Mental health problems often start early and disproportionately affect young people. Poor adolescent mental health can predict educational achievement at school and educational and occupational attainment in adulthood. Many young people attend higher education and have been found to experience a range of mental health issues. The university setting therefore presents a unique opportunity to trial interventions to reduce the burden of mental health problems. Mental Health First Aid (MHFA) aims to train participants to recognise symptoms of mental health problems and assist an individual who may be experiencing a mental health crisis. Training nursing students in MHFA may increase mental health literacy and decrease stigma in the student population. This paper presents a protocol for a trial to examine the efficacy of the MHFA training for students studying nursing at a large university in Perth, Western Australia. Methods/DesignThis randomised controlled trial will follow the CONSORT guidelines. Participants will be randomly allocated to the intervention group (receiving a MHFA training course comprising two face to face 6.5 hour sessions run over two days during the intervention period) or a waitlisted control group (not receiving MHFA training during the study). The source population will be undergraduate nursing students at a large university located in Perth, Western Australia. Efficacy of the MHFA training will be assessed by following the intention-to-treat principle and repeated measures analysis. DiscussionGiven the known burden of mental health disorders among student populations, it is important universities consider effective strategies to address mental health issues. Providing MHFA training to students offers the advantage of increasing mental health literacy, among the student population. Further, students trained in MHFA are likely to utilise these skills in the broader community, when they graduate to the workforce. It is anticipated that this trial will demonstrate the scalability of MHFA in the university environment for pre-service nurses and that implementation of MHFA courses, with comprehensive evaluation, could yield positive improvements in the mental health literacy amongst this target group as well as other tertiary student groups. Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN1261400086165

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI <18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For schoolaged children and adolescents, we report thinness (BMI <2 SD below the median of the WHO growth reference) and obesity (BMI >2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

Aurora A–Selective Inhibitor LY3295668 Leads to Dominant Mitotic Arrest, Apoptosis in Cancer Cells, and Shows Potent Preclinical Antitumor Efficacy

Although Aurora A, B, and C kinases share high sequence similarity, especially within the kinase domain, they function distinctly in cell-cycle progression. Aurora A depletion primarily leads to mitotic spindle formation defects and consequently prometaphase arrest, whereas Aurora B/C inactivation primarily induces polyploidy from cytokinesis failure. Aurora B/C inactivation phenotypes are also epistatic to those of Aurora A, such that the concomitant inactivation of Aurora A and B, or all Aurora isoforms by nonisoform–selective Aurora inhibitors, demonstrates the Aurora B/C-dominant cytokinesis failure and polyploidy phenotypes. Several Aurora inhibitors are in clinical trials for T/B-cell lymphoma, multiple myeloma, leukemia, lung, and breast cancers. Here, we describe an Aurora A–selective inhibitor, LY3295668, which potently inhibits Aurora autophosphorylation and its kinase activity in vitro and in vivo, persistently arrests cancer cells in mitosis, and induces more profound apoptosis than Aurora B or Aurora A/B dual inhibitors without Aurora B inhibition–associated cytokinesis failure and aneuploidy. LY3295668 inhibits the growth of a broad panel of cancer cell lines, including small-cell lung and breast cancer cells. It demonstrates significant efficacy in small-cell lung cancer xenograft and patient-derived tumor preclinical models as a single agent and in combination with standard-of-care agents. LY3295668, as a highly Aurora A–selective inhibitor, may represent a preferred approach to the current pan-Aurora inhibitors as a cancer therapeutic agent

Worldwide trends in underweight and obesity from 1990 to 2022 : a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

A list of authors and their affiliations appears online. A supplementary appendix is herewith attached.Background: Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods: We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI 2 SD above the median). Findings: From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation: The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesity.peer-reviewe

Translation of Sphingosine-1-phosphate-dependent Regulation of Myogenic Tone in Human Resistance Arteries with Heart Failure

Small resistance arteries critically influence tissue perfusion, capillary integrity, total peripheral resistance and systemic blood pressure. They do this in part by adapting diameter to transmural pressure; this intrinsic property of vascular smooth muscle is called the myogenic response. Altered myogenic responses contribute to cardiovascular pathologies, including increased total peripheral resistance in heart failure. However, underlying mechanisms are poorly understood. Sphingosine-1-phosphate (S1P) is a key regulator of the myogenic response in rodents. In mice with heart failure, the myogenic response is increased due to tumour necrosis factor alpha (TNF-alpha) and cystic fibrosis transmembrane conductance regulator (CFTR)-dependent upregulation of S1P signalling. This signalling axis is a potential therapeutic target for heart failure. However, it is unknown if the same mechanisms are operational in patients. As a first step, translation of S1P signalling-dependent regulation of the myogenic response into human resistance arteries is necessary to confirm the therapeutic potential of these new microvascular mechanisms of heart failure. Mesenteric and skeletal muscle resistance arteries were collected from bowel resection and coronary artery bypass graft (CABG) patients, respectively. The presence and functional relevance of S1P signalling was assessed by pressure myography in patients with and without heart failure. Results show molecular expression of S1P signalling components and S1P signalling-dependent regulation of the myogenic response in human resistance arteries. These data also demonstrate potential vascular bed or coronary artery disease-dependent differences in S1P pathway expression and signalling. Correlational analyses do not reveal heart failure-dependent differences in the myogenic response among CABG patients. However, findings indicate that certain co-morbidities and drugs may also influence myogenic tone, meriting further investigation. Overall, this study validates the functional relevance of S1P signalling for the first time in human resistance arteries, forming a foundation for future translation of S1P-dependent mechanisms of heart failure in different patient populations.Ph.D.2017-03-23 00:00:0

Calcium-sensitive Mmechanisms in Vascular Smooth Muscle Cell Cycle Progression as Targets for Therapy

Increased intracellular calcium (Ca2+) is required for vascular smooth muscle cell (VSMC) proliferation through mechanisms that are not well-known. Preventing calmodulin (CaM)-cyclin E interaction with a synthetic peptide inhibits VSMC proliferation in a cyclin E-dependent manner, without increasing de-differentiation or cell death, or affecting re-endothelialization or collagen deposition. Moreover, in situ Ca2+-sensitive phosphorylation and degradation of the cell cycle inhibitor p27Kip1 (p27) in VSMC is specific to G1 and dependent on camodulin kinase-II (CaMK-II) and the proteasome, but not MEK. Lastly, IQGAP1 binding to CaM increases during G1 with no change in total IQGAP1 expression across the cell cycle. Therefore, we determined the clinical potential of an established mechanism (CaM/cyclin E), the existence of a putative mechanism (CaMK-II/p27), and a target novel mechanism (CaM-IQGAP1). Characterization of calcium-sensitive mechanisms of VSMC cycle control could form the basis for new drug-eluting stent agents that have increased selectivity for rapidly dividing VSMC.MAS