Synergistic Communication between CD4+ T Cells and Monocytes Impacts the Cytokine Environment

Physiological cytokine environments arise from factors produced by diverse cell types in coordinated concert. Understanding the contributions of each cell type in the context of cell-cell communication is important for effectively designing disease modifying interventions. Here, we present multi-plexed measurement of 48 cytokines from a coculture system of primary human CD4+ T cells and monocytes across a spectrum of stimuli and for a range of relative T cell/monocyte compositions, coupled with corresponding measurements from PBMCs and plasma from the same donors. Computational analysis of the resulting data-sets elucidated communication-independent and communication-dependent contributions, including both positive and negative synergies. We find that cytokines in cell supernatants were uncorrelated to those found in plasma. Additionally, as an example of positive synergy, production levels of CXCR3 cytokines IP-10 and MIG, depend non-linearly on both IFNγ and TNFα levels in cross-talk between T cells and monocytes. Overall, this work demonstrates that communication between cell types can significantly impact the consequent cytokine environment, emphasizing the value of mixed cell population studies.United States. National Institutes of Health (DP3 DK097681)Institute for Collaborative Biotechnologies (W911NF-09-0001)David H. Koch Institute for Integrative Cancer Research at MITNational Science Foundation (U.S.

Influenza vaccination coverage among an urban pediatric asthma population: Implications for population health

Introduction Asthma is the most common chronic disease in children. Children with asthma are at high risk for complications from influenza; however annual influenza vaccination rates for this population are suboptimal. The overall aim of this study was to describe the characteristics of a high-risk population of children with asthma presenting to an urban pediatric emergency department according to influenza vaccination status. Methods The study was a retrospective chart review of 4355 patients aged 2 to 18 years evaluated in a Michigan pediatric emergency department (PED) between November 1, 2017 and April 30, 2018 with an ICD-10-CM code for asthma (J45.x). Eligible patient PED records were matched with influenza vaccination records for the 2017–2018 influenza season from the Michigan Care Improvement Registry. Geospatial analysis was employed to examine the distribution of influenza vaccination status. Results 1049 patients (30.9%) with asthma seen in the PED had received an influenza vaccine. Influenza vaccination coverage varied by Census Tract, ranging from 10% to \u3e 99%. Most vaccines were administered in a primary care setting (84.3%) and were covered by public insurance (76.8%). The influenza vaccination rate was lowest for children aged 5–11 years (30.0%) and vaccination status was associated with race (p\u3c0.001) and insurance type (p\u3c0.001). Conclusions Identification of neighborhood Census Tract and demographic groups with suboptimal influenza vaccination could guide development of targeted public health interventions to improve vaccination rates in high-risk patients. Given the morbidity and mortality associated with pediatric asthma, a data-driven approach may improve outcomes and reduce healthcare-associated costs for this pediatric population

Medication use by middle-aged and older participants of an exercise study: results from the Brain in Motion study

BACKGROUND: Over the past 50 years, there has been an increase in the utilization of prescribed, over-the-counter (OTC) medications, and natural health products. Although it is known that medication use is common among older persons, accurate data on the patterns of use, including the quantity and type of medications consumed in a generally healthy older population from a Canadian perspective are lacking. In this study, we study the pattern of medication use in a sedentary but otherwise healthy older persons use and determined if there was an association between medication use and aerobic fitness level. METHODS: All participants enrolled in the Brain in Motion study provided the name, formulation, dosage and frequency of any medications they were consuming at the time of their baseline assessment. Maximal aerobic capacity (VO(2)max) was determined on each participant. RESULTS: Two hundred seventy one participants (mean age 65.9 ± 6.5 years; range 55–92; 54.6% females) were enrolled. Most were taking one or more (1+) prescribed medication (n = 204, 75.3%), 1+ natural health product (n = 221, 81.5%) and/or 1+ over-the-counter (OTC) drug (n = 174, 64.2%). The most commonly used prescribed medications were HMG-CoA reductase inhibitors (statins) (n = 52, 19.2%). The most common natural health product was vitamin D (n = 201, 74.2%). For OTC drugs, non-steroidal anti-inflammatories (n = 82, 30.3%) were the most common. Females were more likely than males to take 1+ OTC medications, as well as supplements. Those over 65 years of age were more likely to consume prescription drugs than their counterparts (p ≤ 0.05). Subjects taking more than two prescribed or OTC medications were less physically fit as determined by their VO(2)max. The average daily Vitamin D intake was 1896.3 IU per participant. CONCLUSIONS: Medication use was common in otherwise healthy older individuals. Consumption was higher among females and those older than 65 years. Vitamin D intake was over two-fold higher than the recommended 800 IU/day for older persons, but within the tolerable upper intake of 4,000 IU/day. The appropriateness of the high rate of medication use in this generally healthy population deserves further investigation

Modulation of the severe CD4+ T-cell loss caused by a pathogenic simian–human immunodeficiency virus by replacement of the subtype B vpu with the vpu from a subtype C HIV-1 clinical isolate

AbstractPreviously, we showed that the Vpu protein from subtype C human immunodeficiency virus type 1 (HIV-1) was efficiently targeted to the cell surface, suggesting that this protein has biological properties that differ from the well-studied subtype B Vpu protein. In this study, we have further analyzed the biological properties of the subtype C Vpu protein. Flow cytometric analysis revealed that the subtype B Vpu (strain HXB2) was more efficient at down-regulating CD4 surface expression than the Vpu proteins from four subtype C clinical isolates. We constructed a simian-human immunodeficiency virus virus, designated as SHIVSCVpu, in which the subtype B vpu gene from the pathogenic SHIVKU-1bMC33 was substituted with the vpu from a clinical isolate of subtype C HIV-1 (strain C.96.BW16B01). Cell culture studies revealed that SHIVSCVpu replicated with slightly reduced kinetics when compared with the parental SHIVKU-1bMC33 and that the viral Env and Gag precursor proteins were synthesized and processed similarly compared to the parental SHIVKU-1bMC33. To determine if substitution of the subtype C Vpu protein affected the pathogenesis of the virus, three pig-tailed macaques were inoculated with SHIVSCVpu and circulating CD4+ T-cell levels and viral loads were monitored for up to 44 weeks. Our results show that SHIVSCVpu caused a more gradual decline in the rate of CD4+ T cells in pig-tailed macaques compared to those inoculated with parental subtype B SHIVKU-1bMC33. These results show for the first time that different Vpu proteins of HIV-1 can influence the rate at which CD4+ T-cell loss occurs in the SHIV/pig-tailed macaque model

Red riding on hood: Exploring how galaxy colour depends on environment

Galaxy populations are known to exhibit a strong colour bimodality, corresponding to blue star-forming and red quiescent subpopulations. The relative abundance of the two populations has been found to vary with stellar mass and environment. In this paper, we explore the effect of environment considering different types of measurements. We choose a sample of $49, 911$ galaxies with $0.05 < z < 0.18$ from the Galaxy And Mass Assembly survey. We study the dependence of the fraction of red galaxies on different measures of the local environment as well as the large-scale "geometric" environment defined by density gradients in the surround- ing cosmic web. We find that the red galaxy fraction varies with the environment at fixed stellar mass. The red fraction depends more strongly on local environmental measures than on large-scale geometric environment measures. By comparing the different environmental densities, we show that no density measurement fully explains the observed environmental red fraction variation, suggesting the different measures of environmental density contain different information. We test whether the local environmental measures, when combined together, can explain all the observed environmental red fraction variation. The geometric environment has a small residual effect, and this effect is larger for voids than any other type of geometric environment. This could provide a test of the physics applied to cosmological-scale galaxy evolution simulations as it combines large-scale effects with local environmental impact.Comment: Accepted for publication in MNRAS; 16 pages; 10 figures; 2 tables

Detection and Identification of Salmonella enterica, Escherichia coli, and Shigella spp. via PCR-ESI-MS: Isolate Testing and Analysis of Food Samples

An assay to identify the common food-borne pathogens Salmonella, Escherichia coli, Shigella, and Listeria monocytogenes was developed in collaboration with Ibis Biosciences (a division of Abbott Molecular) for the Plex-ID biosensor system, a platform that uses electrospray ionization mass spectroscopy (ESI-MS) to detect the base composition of short PCR amplicons. The new food-borne pathogen (FBP) plate has been experimentally designed using four gene segments for a total of eight amplicon targets. Initial work built a DNA base count database that contains more than 140 Salmonella enterica, 139 E. coli, 11 Shigella, and 36 Listeria patterns and 18 other Enterobacteriaceae organisms. This assay was tested to determine the scope of the assay\u27s ability to detect and differentiate the enteric pathogens and to improve the reference database associated with the assay. More than 800 bacterial isolates of S. enterica, E. coli, and Shigella species were analyzed. Overall, 100% of S. enterica, 99% of E. coli, and 73% of Shigella spp. were detected using this assay. The assay was also able to identify 30% of the S. enterica serovars to the serovar level. To further characterize the assay, spiked food matrices and food samples collected during regulatory field work were also studied. While analysis of preenrichment media was inconsistent, identification of S. enterica from selective enrichment media resulted in serovar-level identifications for 8 of 10 regulatory samples. The results of this study suggest that this high-throughput method may be useful in clinical and regulatory laboratories testing for these pathogens

Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet

Objectives:&nbsp;Elevated plasma glucagon is an early symptom of diabetes, occurring in subjects with impaired glucose regulation. Here, we explored alpha-cell function in female mice fed a high-fat diet (HFD)&mdash;a widely used mouse model of prediabetes. Methods:&nbsp;We fed female mice expressing the Ca2+&nbsp;indicator GCaMP3 specifically in alpha-cells an HFD or control (CTL) diet. We then conducted&nbsp;in&nbsp;vivo&nbsp;phenotyping of these mice, as well as experiments on isolated (ex&nbsp;vivo) islets and in the&nbsp;in situ&nbsp;perfused pancreas. Results:&nbsp;In&nbsp;vivo,&nbsp;HFD-fed mice exhibited increased fed plasma glucagon levels and a reduced response to elevations in plasma glucose. Glucagon secretion from isolated islets and in the perfused mouse pancreas was elevated under both hypo- and hyperglycaemic conditions. In mice fed a CTL diet, increasing glucose reduced intracellular Ca2+&nbsp;([Ca2+]i) (oscillation frequency and amplitude). This effect was also observed in HFD mice; however, both the frequency and amplitude of the [Ca2+]i&nbsp;oscillations were higher than those in CTL alpha-cells. Given that alpha-cells are under strong paracrine control from neighbouring somatostatin-secreting delta-cells, we hypothesised that this elevation of alpha-cell output was due to a lack of somatostatin (SST) secretion. Indeed, SST secretion in isolated islets from HFD mice was reduced but exogenous SST also failed to suppress glucagon secretion and [Ca2+]i&nbsp;activity from HFD alpha-cells, in contrast to observations in CTL mice. Conclusions:&nbsp;These findings suggest that reduced delta-cell function, combined with intrinsic changes in alpha-cell sensitivity to somatostatin, accounts for the hyperglucagonaemia in mice fed an HFD.</p

BST-2 mediated restriction of simian–human immunodeficiency virus

AbstractPathogenic simian–human immunodeficiency viruses (SHIV) contain HIV-1 Vpu and SIV Nef, both shown to counteract BST-2 (HM1.24; CD317; tetherin) inhibition of virus release in a species-specific manner. We show that human and pig-tailed BST-2 (ptBST-2) restrict SHIV. We found that sequential “humanization” of the transmembrane domain (TMD) of the pig-tailed BST-2 (ptBST-2) protein resulted in a fluctuation in sensitivity to HIV-1 Vpu. Our results also show that the length of the TMD in human and ptBST-2 proteins is important for BST-2 restriction and susceptibility to Vpu. Taken together, our results emphasize the importance of tertiary structure in BST-2 antagonism and suggests that the HIV-1 Vpu transmembrane domain may have additional functions in vivo unrelated to BST-2 antagonism

Identifying factors which influence eating disorder risk during behavioral weight management: A consensus study

This study aimed to understand clinician, researcher and consumer views regarding factors which influence eating disorder (ED) risk during behavioral weight management, including individual risk factors, intervention strategies and delivery features. Eighty-seven participants were recruited internationally through professional and consumer organizations and social media and completed an online survey. Individual characteristics, intervention strategies (5-point scale) and delivery features (important/unimportant/unsure) were rated. Participants were mostly women (n = 81), aged 35-49 y, from Australia or United States, were clinicians and/or reported lived experience of overweight/obesity and/or ED. There was agreement (64% to 99%) that individual characteristics were relevant to ED risk, with history of ED, weight-based teasing/stigma and weight bias internalization having the highest agreement. Intervention strategies most frequently rated as likely to increase ED risk included those with a focus on weight, prescription (structured diets, exercise plans) and monitoring strategies, e.g., calorie counting. Strategies most frequently rated as likely to decrease ED risk included having a health focus, flexibility and inclusion of psychosocial support. Delivery features considered most important were who delivered the intervention (profession, qualifications) and support (frequency, duration). Findings will inform future research to quantitatively assess which of these factors predict eating disorder risk, to inform screening and monitoring protocols

A Randomised, Double-Blind, Controlled Vaccine Efficacy Trial of DNA/MVA ME-TRAP Against Malaria Infection in Gambian Adults

BACKGROUND: Many malaria vaccines are currently in development, although very few have been evaluated for efficacy in the field. Plasmodium falciparum multiple epitope (ME)– thrombospondin-related adhesion protein (TRAP) candidate vaccines are designed to potently induce effector T cells and so are a departure from earlier malaria vaccines evaluated in the field in terms of their mechanism of action. ME-TRAP vaccines encode a polyepitope string and the TRAP sporozoite antigen. Two vaccine vectors encoding ME-TRAP, plasmid DNA and modified vaccinia virus Ankara (MVA), when used sequentially in a prime-boost immunisation regime, induce high frequencies of effector T cells and partial protection, manifest as delay in time to parasitaemia, in a clinical challenge model. METHODS AND FINDINGS: A total of 372 Gambian men aged 15–45 y were randomised to receive either DNA ME-TRAP followed by MVA ME-TRAP or rabies vaccine (control). Of these men, 296 received three doses of vaccine timed to coincide with the beginning of the transmission season (141 in the DNA/MVA group and 155 in the rabies group) and were followed up. Volunteers were given sulphadoxine/pyrimethamine 2 wk before the final vaccination. Blood smears were collected weekly for 11 wk and whenever a volunteer developed symptoms compatible with malaria during the transmission season. The primary endpoint was time to first infection with asexual P. falciparum. Analysis was per protocol. DNA ME-TRAP and MVA ME-TRAP were safe and well-tolerated. Effector T cell responses to a non-vaccine strain of TRAP were 50-fold higher postvaccination in the malaria vaccine group than in the rabies vaccine group. Vaccine efficacy, adjusted for confounding factors, was 10.3% (95% confidence interval, −22% to +34%; p = 0.49). Incidence of malaria infection decreased with increasing age and was associated with ethnicity. CONCLUSIONS: DNA/MVA heterologous prime-boost vaccination is safe and highly immunogenic for effector T cell induction in a malaria-endemic area. But despite having produced a substantial reduction in liver-stage parasites in challenge studies of non-immune volunteers, this first generation T cell–inducing vaccine was ineffective at reducing the natural infection rate in semi-immune African adults