Discovery of functionally selective C5aR2 ligands: novel modulators of C5a signalling.

The complement cascade is comprised of a highly sophisticated network of innate immune proteins that are activated in response to invading pathogens or tissue injury. The complement activation peptide, C5a, binds two seven transmembrane receptors, namely the C5a receptor 1 (C5aR1) and C5a receptor 2 (C5aR2, or C5L2). C5aR2 is a non-G-protein-signalling receptor whose biological role remains controversial. Some of this controversy arises owing to the lack of selective ligands for C5aR2. In this study, a library of 61 peptides based on the C-terminus of C5a was assayed for the ability to selectively modulate C5aR2 function. Two ligands (P32 and P59) were identified as functionally selective C5aR2 ligands, exhibiting selective recruitment of β-arrestin 2 via C5aR2, partial inhibition of C5a-induced ERK1/2 activation and lipopolysaccharide-stimulated interleukin-6 release from human monocyte-derived macrophages. Importantly, neither ligand could induce ERK1/2 activation or inhibit C5a-induced ERK1/2 activation via C5aR1 directly. Finally, P32 inhibited C5a-mediated neutrophil mobilisation in wild-type, but not C5aR2(-/-) mice. These functionally selective ligands for C5aR2 are novel tools that can selectively modulate C5a activity in vitro and in vivo, and thus will be valuable tools to interrogate C5aR2 function.Immunology and Cell Biology advance online publication, 17 May 2016; doi:10.1038/icb.2016.43

Modelling the response of phytoplankton in a shallow lake (Loch Leven, UK) to changes in lake retention time and water temperature.

The phytoplankton community of Loch Leven in 2005 was modelled and subjected to a combination of different flushing rates and water temperatures in order to assess the lake’s sensitivity to these two climatic drivers. Whilst the simulated annual mean total chlorophyll a proved relatively insensitive to these changes, at the species level marked changes were recorded. Some species responded positively to increased temperature (e.g. Aulacoseira), some negatively (e.g. Asterionella), whilst others were negatively affected by increased flow (e.g. Aphanocapsa) and others enhanced (e.g. Stephanodiscus). However, this relationship with flow was season dependent with, for example, a simulated increase in summer inflows actually benefiting some species through increased nutrient supply, whereas an equivalent increase in flow in wetter seasons would have negatively affected those species (i.e. through flushing loss). Overall, the simulations showed that the range of species types simulated in the community was sufficient for one species to always benefit from the changing niches created by the multiple climatic drivers applied in this study. The level of exploitation by such a species was only constrained by the nutrient carrying capacity of the system, which led to the overall dampened response in the total chlorophyll a measure, both at the annual and season scale. Thus, whilst overall biomass showed relatively little reaction to the two climatic drivers tested, the phytoplankton community composition responded markedly

Characterisation and evaluation of the regenerative capacity of Stro-4+ enriched bone marrow mesenchymal stromal cells using bovine extracellular matrix hydrogel and a novel biocompatible melt electro-written medical-grade polycaprolactone scaffold

Many skeletal tissue regenerative strategies centre around the multifunctional properties of bone marrow derived stromal cells (BMSC) or mesenchymal stem/stromal cells (MSC)/bone marrow derived skeletal stem cells (SSC). Specific identification of these particular stem cells has been inconclusive. However, enriching these heterogeneous bone marrow cell populations with characterised skeletal progenitor markers has been a contributing factor in successful skeletal bone regeneration and repair strategies. In the current studies we have isolated, characterised and enriched ovine bone marrow mesenchymal stromal cells (oBMSCs) using a specific antibody, Stro-4, examined their multipotential differentiation capacity and, in translational studies combined Stro-4+ oBMSCs with a bovine extracellular matrix (bECM) hydrogel and a biocompatible melt electro-written medical-grade polycaprolactone scaffold, and tested their bone regenerative capacity in a small in vivo, highly vascularised, chick chorioallantoic membrane (CAM) model and a preclinical, critical-sized ovine segmental tibial defect model.Proliferation rates and CFU-F formation were similar between unselected and Stro-4+ oBMSCs. Col1A1, Col2A1, mSOX-9, PPARG gene expression were upregulated in respective osteogenic, chondrogenic and adipogenic culture conditions compared to basal conditions with no significant difference between Stro-4+ and unselected oBMSCs. In contrast, proteoglycan expression, alkaline phosphatase activity and adipogenesis were significantly upregulated in the Stro-4+ cells. Furthermore, with extended cultures, the oBMSCs had a predisposition to maintain a strong chondrogenic phenotype. In the CAM model Stro-4+ oBMSCs/bECM hydrogel was able to induce bone formation at a femur fracture site compared to bECM hydrogel and control blank defect alone. Translational studies in a critical-sized ovine tibial defect showed autograft samples contained significantly more bone, (4250.63 mm3, SD = 1485.57) than blank (1045.29 mm3, SD = 219.68) ECM-hydrogel (1152.58 mm3, SD = 191.95) and Stro-4+/ECM-hydrogel (1127.95 mm3, SD = 166.44) groups.Stro-4+ oBMSCs demonstrated a potential to aid bone repair in vitro and in a small in vivo bone defect model using select scaffolds. However, critically, translation to a large related preclinical model demonstrated the complexities of bringing small scale reported stem-cell material therapies to a clinically relevant model and thus facilitate progression to the clinic

Towards a Simple Model of Compressible Alfvenic Turbulence

A simple model collisionless, dissipative, compressible MHD (Alfvenic) turbulence in a magnetized system is investigated. In contrast to more familiar paradigms of turbulence, dissipation arises from Landau damping, enters via nonlinearity, and is distributed over all scales. The theory predicts that two different regimes or phases of turbulence are possible, depending on the ratio of steepening to damping coefficient (m_1/m_2). For strong damping (|m_1/m_2|<1), a regime of smooth, hydrodynamic turbulence is predicted. For |m_1/m_2|>1, steady state turbulence does not exist in the hydrodynamic limit. Rather, spikey, small scale structure is predicted.Comment: 6 pages, one figure, REVTeX; this version to be published in PRE. For related papers, see http://sdphpd.ucsd.edu/~medvedev/papers.htm

Factors associated with depression and anxiety in the adult population of Qatar after the first COVID-19 wave: a cross-sectional study

There is limited data from Arabic-speaking countries on risk factors for depression and anxiety during the COVID-19 pandemic. Country-specific data is necessary given differences in culture, demographics, and COVID-19 infection and mortality rates. The main purpose of the study is to identify the factors associated with symptoms of depression-anxiety in the adult population of Qatar during the first year of the COVID-19 pandemic. We conducted a cross-sectional online survey in Qatar between July and December 2020 after Qatar’s first COVID-19 wave and before the beginning of the second wave. Depression-anxiety was defined as a cut-off of 20 or higher on the Patient Health Questionnaire-Anxiety Depression Scale (PHQ-ADS). Of 1138 participants, 71.0% were female, 69.0% Arabs, 70.0% Non-Qataris, and 77.0% were < 40 years (the median age in Qatar is 32 years). In a fully-adjusted model, six variables were significantly associated with moderate-to-severe levels of depression or anxiety on the PHQ-ADS; Arab ethnicity (OR = 1.67, p = 0.026), never married versus married (OR = 1.69, p = 0.015), prior history of psychiatric disorder versus no history (OR = 1.80, p = 0.009), increased worries due to social media use for COVID-related news/updates (OR = 1.72, p = 0.003), a history of COVID-19 (OR = 1.76, p = 0.039), loneliness (OR = 1.91, p < 0.001), and lower levels of religiosity (OR = 0.96, p = 0.039). These associations also pertained in the reduced model, with the exception of religiosity which was only marginally statistically significant (OR = 0.97, p = 0.055). The potential risk factors identified may assist with anxiety and depression prevention in future COVID-19 waves, and similar national events, and assist with early intervention to treat sufferers

Microparticles for sustained growth factor delivery in the regeneration of critically-sized segmental tibial bone defects

The Publisher's final version can be found by following the DOI link. Open access article.This study trialled the controlled delivery of growth factors within a biodegradable scaffold in a large segmental bone defect model. We hypothesised that co-delivery of vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) followed by bone morphogenetic protein-2 (BMP-2) could be more effective in stimulating bone repair than the delivery of BMP-2 alone. Poly(lactic-co-glycolic acid) (PLGA ) based microparticles were used as a delivery system to achieve a controlled release of growth factors within a medical-grade Polycaprolactone (PCL) scaffold. The scaffolds were assessed in a well-established preclinical ovine tibial segmental defect measuring 3 cm. After six months, mechanical properties and bone tissue regeneration were assessed. Mineralised bone bridging of the defect was enhanced in growth factor treated groups. The inclusion of VEGF and PDGF (with BMP-2) had no significant effect on the amount of bone regeneration at the six-month time point in comparison to BMP-2 alone. However, regions treated with VEGF and PDGF showed increased vascularity. This study demonstrates an effective method for the controlled delivery of therapeutic growth factors in vivo, using microparticles

ROP: dumpster diving in RNA-sequencing to find the source of 1 trillion reads across diverse adult human tissues.

High-throughput RNA-sequencing (RNA-seq) technologies provide an unprecedented opportunity to explore the individual transcriptome. Unmapped reads are a large and often overlooked output of standard RNA-seq analyses. Here, we present Read Origin Protocol (ROP), a tool for discovering the source of all reads originating from complex RNA molecules. We apply ROP to samples across 2630 individuals from 54 diverse human tissues. Our approach can account for 99.9% of 1 trillion reads of various read length. Additionally, we use ROP to investigate the functional mechanisms underlying connections between the immune system, microbiome, and disease. ROP is freely available at https://github.com/smangul1/rop/wiki

Marijuana use associations with pulmonary symptoms and function in Tobacco smokers enrolled in the Subpopulations and Intermediate Outcome Measures in COPD study (SPIROMICS)

Background: Marijuana is often smoked via a filterless cigarette and contains similar chemical makeup as smoked tobacco. There are few publications describing usage patterns and respiratory risks in older adults or in those with chronic obstructive pulmonary disease (COPD). Methods: A cross-sectional analysis of current and former tobacco smokers from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) study assessed associations between marijuana use and pulmonary outcomes. Marijuana use was defined as never, former (use over 30 days ago), or current (use within 30 days). Respiratory health was assessed using quantitative high-resolution computed tomography (HRCT) scans, pulmonary function tests and questionnaire responses about respiratory symptoms. Results: Of the total 2304 participants, 1130 (49%) never, 982 (43%) former, and 192 (8%) current marijuana users were included. Neither current nor former marijuana use was associated with increased odds of wheeze (odds ratio [OR] 0.87, OR 0.97), cough (OR 1.22; OR 0.93) or chronic bronchitis (OR 0.87; OR 1.00) when compared to never users. Current and former marijuana users had lower quantitative emphysema (P=0.004, P=0.03), higher percent predicted forced expiratory volume in 1 second (FEV1%) (P < 0.001, P < 0.001), and percent predicted forced vital capacity (FVC%) (p < 0.001, P < 0.001). Current marijuana users exhibited higher total tissue volume (P=0.003) while former users had higher air trapping (P < 0.001) when compared to never marijuana users. Conclusions: Marijuana use was found to have little to no association with poor pulmonary health in older current and former tobacco smokers after adjusting for covariates. Higher forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) was observed among current marijuana users. However, higher joint years was associated with more chronic bronchitis symptoms (e.g., wheeze), and this study cannot determine if long-term heavy marijuana smoking in the absence of tobacco smoking is associated with lung symptoms, airflow obstruction, or emphysema, particularly in those who have never smoked tobacco cigarettes

Examining Contextual Factors and Individual Value Dimensions of Healthcare Providers Intention to Adopt Electronic Health Technologies in Developing Countries

Part 5: Research in ProgressInternational audienceDespite substantial research on electronic health (e-Health) adoption, there still exist vast differences between resource-rich and resource-poor populations regarding Information Technology adoption. To help bridge the technological gulf between developed and developing countries, this research-in-progress paper examines healthcare providers’ intention to adopt e-health technologies from two perspectives 1) contextual factors (i.e. specific to developing world settings) and 2) individual value dimensions (i.e. cultural, utilitarian, social and personal). The primary output of this paper is a theoretical model merging both the contextual factors and value dimensions; this forms a strong baseline to examine and help ensure the successful adoption of e-Health technologies within developing countries. Future research will be performed to validate the model developed in this paper, with a specific focus on mobile Health in Malawi, Africa