Metabolomic profiling of macrophages determines the discrete metabolomic signature and metabolomic interactome triggered by polarising immune stimuli

Priming and activating immune stimuli have profound effects on macrophages, however, studies generally evaluate stimuli in isolation rather than in combination. In this study we have investigated the effects of pro-inflammatory and anti-inflammatory stimuli either alone or in combination on macrophage metabolism. These stimuli include host factors such as IFNγ and ovalbumin-immunoglobulin immune complexes, or pathogen factors such as LPS. Untargeted LC-MS based metabolomics provided an in-depth profile of the macrophage metabolome, and revealed specific changes in metabolite abundance upon either individual stimuli or combined stimuli. Here, by factoring in an interaction term in the linear model, we define the metabolome interactome. This approach allowed us to determine whether stimuli interact in a synergistic or antagonistic manner. In conclusion this study demonstrates a robust approach to interrogate immune-metabolism, especially systems that model host-pathogen interactions

Healthcare avoidance due to anticipated discrimination among transgender people: A call to create trans-affirmative environments

Transgender people encounter interpersonal and structural barriers to healthcare access that contribute to their postponement or avoidance of healthcare, which can lead to poor physical and mental health outcomes. Using the 2015 U.S. Transgender Survey, this study examined avoidance of healthcare due to anticipated discrimination among transgender adults aged 25 to 64 (N ¼ 19,157). Multivariable logistic regression analysis was conducted to test whether gender identity/expression, socio-demographic, and transgender-specific factors were associated with healthcare avoidance. Almost one-quarter of the sample (22.8%) avoided healthcare due to anticipated discrimination. Transgender men had increased odds of healthcare avoidance (AOR ¼ 1.32, 95% CI ¼ 1.21–1.45) relative to transgender women. Living in poverty (AOR ¼ 1.52, 95% CI ¼ 1.40–1.65) and visual non-conformity (AOR ¼ 1.48, 95% CI ¼ 1.33–1.66) were significant risk factors. Having health insurance (AOR ¼ 0.87, 95% CI ¼ 0.79–0.96) and disclosure of transgender identity (AOR ¼ 0.77, 95% CI ¼ 0.68–0.87) were protective against healthcare avoidance. A significant interaction of gender identity/expression with health insurance was found; having health insurance moderated the association between gender identity/expression and healthcare avoidance. Providers should consider gender differences, socio-demographic, and transgender-specific factors to improve accessibility of services to transgender communities. A multi-level and multifaceted approach should be used to create safe, trans-affirmative environments in health systems

Comparison of high-specific-activity ultratrace 123/131I-MIBG and carrier-added 123/131I-MIBG on efficacy, pharmacokinetics, and tissue distribution

Metaiodobenzylguanidine (MIBG) is an enzymatically stable synthetic analog of norepinephrine that when radiolabled with diagnostic ((123)I) or therapeutic ((131)I) isotopes has been shown to concentrate highly in sympathetically innervated tissues such as the heart and neuroendocrine tumors that possesses high levels of norepinephrine transporter (NET). As the transport of MIBG by NET is a saturable event, the specific activity of the preparation may have dramatic effects on both the efficacy and safety of the radiodiagnostic/radiotherapeutic. Using a solid labeling approach (Ultratrace), noncarrier-added radiolabeled MIBG can be efficiently produced. In this study, specific activities of >1200 mCi/micromol for (123)I and >1600 mCi/micromol for (131)I have been achieved. A series of studies were performed to assess the impact of cold carrier MIBG on the tissue distribution of (123/131)I-MIBG in the conscious rat and on cardiovascular parameters in the conscious instrumented dog. The present series of studies demonstrated that the carrier-free Ultratrace MIBG radiolabeled with either (123)I or (131)I exhibited similar tissue distribution to the carrier-added radiolabeled MIBG in all nontarget tissues. In tissues that express NETs, the higher the specific activity of the preparation the greater will be the radiopharmaceutical uptake. This was reflected by greater efficacy in the mouse neuroblastoma SK-N-BE(2c) xenograft model and less appreciable cardiovascular side-effects in dogs when the high-specific-activity radiopharmaceutical was used. The increased uptake and retention of Ultratrace (123/131)I-MIBG may translate into a superior diagnostic and therapeutic potential. Lastly, care must be taken when administering therapeutic doses of the current carrier-added (131)I-MIBG because of its potential to cause adverse cardiovascular side-effects, nausea, and vomiting

Cosmological Plebanski theory

We consider the cosmological symmetry reduction of the Plebanski action as a toy-model to explore, in this simple framework, some issues related to loop quantum gravity and spin-foam models. We make the classical analysis of the model and perform both path integral and canonical quantizations. As for the full theory, the reduced model admits two types of classical solutions: topological and gravitational ones. The quantization mixes these two solutions, which prevents the model to be equivalent to standard quantum cosmology. Furthermore, the topological solution dominates at the classical limit. We also study the effect of an Immirzi parameter in the model.Comment: 20 page

Evaluation of Restaurant Menus to Determine the Availability of Healthy Food Options and Guide Community Transformation Grant Activities in Massachusetts

INTRODUCTION. The availability of healthy menu options in restaurants is an important factor in the prevention of obesity. The Mass in Motion Initiative and two Community Transformation Grant (CTG) projects are conducting statewide longitudinal surveys to determine the availability of healthy food in restaurants in the state of Massachusetts. METHODS. The Community Nutrition Environment Evaluation Data System-Restaurant (C-NEEDS-R) was developed for food environment surveillance. C-NEEDS-R takes into account seasonal and geographic variations in food supplies, cultural relevance, and USDA dietary recommendations. Between summer 2012 and winter 2013, 506 restaurants in 36 Massachusetts towns and cities were surveyed and analyzed. Through menu and site evaluation, the availability of healthy entrees was examined for each restaurant, and the total number of healthy entrees as well as the percent of healthy entrees was calculated for each restaurant. For each municipality, the average number and average percentage of healthy entrees for restaurants within the community was also calculated. RESULTS. The surveyed restaurants had average 3.2 healthy entrees on the menu, accounting for 13.4% of the total number of entrees available. The percentage of healthy options varied widely by restaurant and restaurant type, ranging from 0 to 84%, and only 15 of the 506 surveyed restaurants ( DISCUSSION. As noted, menu evaluation demonstrated that the large majority of the surveyed restaurants had few healthy entrees, indicating a need to increase availability of healthy options. Analysis of restaurant- and community-level variations in availability is useful for CTG programs to formulate and prioritize interventions. Future longitudinal surveys of food stores in the intervention and control communities will help evaluate the effectiveness of CTG interventions

High-throughput testing in head and neck squamous cell carcinoma identifies agents with preferential activity in human papillomavirus-positive or negative cell lines.

Head and neck squamous cell carcinoma (HNSCC) is a common cancer diagnosis worldwide. Despite advances in treatment, HNSCC has very poor survival outcomes, emphasizing an ongoing need for development of improved therapeutic options. The distinct tumor characteristics of human papillomavirus (HPV)-positive vs. HPV-negative disease necessitate development of treatment strategies tailored to tumor HPV-status. High-throughput robotic screening of 1,433 biologically and pharmacologically relevant compounds at a single dose (4 μM) was carried out against 6 HPV-positive and 20 HPV-negative HNSCC cell lines for preliminary identification of therapeutically relevant compounds. Statistical analysis was further carried out to differentiate compounds with preferential activity against cell lines stratified by the HPV-status. These analyses yielded 57 compounds with higher activity in HPV-negative cell lines, and 34 with higher-activity in HPV-positive ones. Multi-point dose-response curves were generated for six of these compounds (Ryuvidine, MK-1775, SNS-032, Flavopiridol, AZD-7762 and ARP-101), confirming Ryuvidine to have preferential potency against HPV-negative cell lines, and MK-1775 to have preferential potency against HPV-positive cell lines. These data comprise a valuable resource for further investigation of compounds with therapeutic potential in the HNSCC

Repurposing Albendazole: new potential as a chemotherapeutic agent with preferential activity against HPV-negative head and neck squamous cell cancer.

Albendazole is an anti-helminthic drug that has been shown to exhibit anti-cancer properties, however its activity in head and neck squamous cell cancer (HNSCC) was unknown. Using a series of in vitro assays, we assessed the ability of albendazole to inhibit proliferation in 20 HNSCC cell lines across a range of albendazole doses (1 nM-10 μM). Cell lines that responded to treatment were further examined for cell death, inhibition of migration and cell cycle arrest. Thirteen of fourteen human papillomavirus-negative HNSCC cell lines responded to albendazole, with an average IC50 of 152 nM. In contrast, only 3 of 6 human papillomavirus-positive HNSCC cell lines responded. Albendazole treatment resulted in apoptosis, inhibition of cell migration, cell cycle arrest in the G2/M phase and altered tubulin distribution. Normal control cells were not measurably affected by any dose tested. This study indicates that albendazole acts to inhibit the proliferation of human papillomavirus-negative HNSCC cell lines and thus warrants further study as a potential chemotherapeutic agent for patients suffering from head and neck cancer

Gulls as Sources of Environmental Contamination by Colistin-resistant Bacteria

In 2015, the mcr-1 gene was discovered in Escherichia coli in domestic swine in China that conferred resistance to colistin, an antibiotic of last resort used in treating multi-drug resistant bacterial infections in humans. Since then, mcr-1 was found in other human and animal populations, including wild gulls. Because gulls could disseminate the mcr-1 gene, we conducted an experiment to assess whether gulls are readily colonized with mcr-1 positive E. coli, their shedding patterns, transmission among conspecifics, and environmental deposition. Shedding of mcr-1 E. coli by small gull flocks followed a lognormal curve and gulls shed one strain \u3e101 log10 CFU/g in their feces for 16.4 days, which persisted in the environment for 29.3 days. Because gulls are mobile and can shed antimicrobial-resistant bacteria for extended periods, gulls may facilitate transmission of mcr-1 positive E. coli to humans and livestock through fecal contamination of water, public areas and agricultural operations