Analysis of the interaction between tryptophan-related compounds and ATP-binding cassette transporter G2 (ABCG2) using targeted metabolomics

ATP-binding cassette transporter G2 (ABCG2) is involved in the secretion of several compounds in milk. The in vitro and in vivo interactions between tryptophan-related compounds and ABCG2 were investigated. The tryptophan metabolome was determined by liquid chromatography-tandem mass spectrometry in milk and plasma from wild-type and Abcg2-/- mice as well as dairy cows carrying the ABCG2 Y581S polymorphism (Y/S) and noncarrier animals (Y/Y). The milk-to-plasma ratios of tryptophan, kynurenic acid, kynurenine, anthranilic acid, and xanthurenic acid were higher in wild-type mice than in Abcg2-/- mice. The ratio was 2-fold higher in Y/S than in Y/Y cows for kynurenine. In vitro transport assays confirmed that some of these compounds were in vitro substrates of the transporter and validated the differences observed between the two variants of the bovine protein. These findings show that the secretion of metabolites belonging to the kynurenine pathway into milk is mediated by ABCG2.SIThis study was supported by the research projects AGL2015-65626-R (MINECO/FEDER, UE) and RTI2018-100903-B-I00 (AEI/FEDER, UE), predoctoral grants from the Ministry of Economy, Industry, and Competitiveness (BES-2016-077235 grant to AMGL), and grants from the Spanish Ministry of Education, Culture, and Sport (FPU14/05131 grant to DGM). Funding was also obtained from a research contract for OJP from the Spanish Health Institute Carlos III (CPII16/00027

Virtual Laboratory Methodologies in Electrical Engineering

Non

Circulating anthocyanin metabolites mediate vascular benefits of blueberries:insights from randomized controlled trials, metabolomics, and nutrigenomics

Potential health benefits of blueberries may be due to vascular effects of anthocyanins which predominantly circulate in blood as phenolic acid metabolites. We investigated which role blueberry anthocyanins and circulating metabolites play in mediating improvements in vascular function and explore potential mechanisms using metabolomics and nutrigenomics. Purified anthocyanins exerted a dose-dependent improvement of endothelial function in healthy humans, as measured by flow-mediated dilation (FMD). The effects were similar to those of blueberries containing similar amounts of anthocyanins while control drinks containing fiber, minerals, or vitamins had no significant effect. Daily 1-month blueberry consumption increased FMD and lowered 24h-ambulatory-systolic-blood-pressure. Of the 63 anthocyanin plasma metabolites quantified, 14 and 17 correlated with acute and chronic FMD improvements, respectively. Injection of these metabolites improved FMD in mice. Daily blueberry consumption led to differential expression (>1.2-fold) of 608 genes and 3 microRNAs, with Mir-181c showing a 13-fold increase in peripheral blood mononuclear cells. Patterns of 13 metabolites were independent predictors of gene expression changes and pathway enrichment analysis revealed significantly modulated biological processes involved in cell adhesion, migration, immune response, and cell differentiation. Our results identify anthocyanin metabolites as major mediators of vascular bioactivities of blueberries and changes of cellular gene programs

Demonstrating HIVE and HIVE-ES: Supporting Term Browsing and Automatic Text Indexing with Linked Open Vocabularies

Abstract y presentación presentados en el WorkshopThe HIVE (Helping Interdisciplinary Vocabulary Engineering) and HIVE-España (ES) projects both support dynamic, automatic metadata generation using multiple vocabularies. This demonstration will present both the HIVE and HIVE-ES projects and showcase the overarching HIVE framework and functionalities, and give insight into the broader issues relating to linked open vocabularies—LOV. HIVE relies on the Simple Knowledge Organization System (SKOS) and the Kea++/Maui algorithms, which enable more sophisticated terminological selection compared to frequency counts. Baseline studies provide some positive, yet mixed results, and a framework for further study. The adequacy of HIVE and HIVE-ES's searching and browsing capabilities are required to be addressed; and the research should target SKOS use for different types of vocabularies (thesaurus vs. subject heading lists) and, specially on the performance of the text indexing algorithms used depending on the type of vocabulary, the features of the training set documents and those indexed, and the language of all of them

Prospects of Mobile Search

Search faces (at least) two major challenges. One is to improve efficiency of retrieving relevant content for all digital formats (images, audio, video, 3D shapes, etc). The second is making relevant information retrievable in a range of platforms, particularly in high diffusion ones as mobiles. The two challenges are interrelated but distinct. This report aims at assessing the potential of future Mobile Search. Two broad groups of search-based applications can be identified. The first one is the adaptation and emulation of web search processes and services to the mobile environment. The second one is services exploiting the unique features of the mobile devices and the mobile environments. Examples of these context-aware services include location-based services or interfacing to the internet of things (RFID networks). The report starts by providing an introduction to mobile search. It highlights differences and commonalities with search technologies on other platforms (Chapter 1). Chapter 2 is devoted to the supply side of mobile search markets. It describes mobile markets, presents key figures and gives an outline of main business models and players. Chapter 3 is dedicated to the demand side of the market. It studies users¿ acceptance and demand using the results on a case study in Sweden. Chapter 4 presents emerging trends in technology and markets that could shape mobile search. It is the author's view after discussing with many experts. One input to this discussion was the analysis of on forward-looking scenarios for mobile developed by the authors (Chapter 5). Experts were asked to evaluate these scenarios. Another input was a questionnaire to which 61 experts responded. Drivers, barriers and enablers for mobile search have been synthesised into SWOT analysis. The report concludes with some policy recommendations in view of the likely socio-economic implications of mobile search in Europe.JRC.DG.J.4-Information Societ

Clinical Usefulness Of Sars-Cov-2 Rapid Antigen Tests In Adults During High Prevalence Community Outbreaks

We evaluated performance of Abbott PanBio® COVID-19 Rapid Antigen Test Device (RATD) to detect SARS-CoV-2 infection in adults during high prevalence COVID-19 outbreaks. We found high accuracy in correct diagnosis (88% CI 85-91%, p<0.05) regardless of gender, presence of symptoms, disease timeline. Test sensitivity appeared to increase with age, specificity seemed to decline. Best diagnostic accuracy was obtained in middle-aged adults (94% CI 89-97%, p<0.05), but remained high through all ages. These results support RATD as a reliable measure to determine isolation of infected individuals during outbreaks. More studies are needed to assess RATD performance in low prevalence post-vaccination scenarios.http://deepblue.lib.umich.edu/bitstream/2027.42/166596/1/AFM-177-21_PP.pdfDescription of AFM-177-21_PP.pdf : Main ArticleSEL

Deciphering the quality of SARS-CoV-2 specific T-cell response associated with disease severity, immune memory and heterologous response

SARS-CoV-2 specific T-cell response has been associated with disease severity, immune memory and heterologous response to endemic coronaviruses. However, an integrative approach combining a comprehensive analysis of the quality of SARS-CoV-2 specific T-cell response with antibody levels in these three scenarios is needed. In the present study, we found that, in acute infection, while mild disease was associated with high T-cell polyfunctionality biased to IL-2 production and inversely correlated with anti-S IgG levels, combinations only including IFN-γ with the absence of perforin production predominated in severe disease. Seven months after infection, both non-hospitalised and previously hospitalised patients presented robust anti-S IgG levels and SARS-CoV-2 specific T-cell response. In addition, only previously hospitalised patients showed a T-cell exhaustion profile. Finally, combinations including IL-2 in response to S protein of endemic coronaviruses were the ones associated with SARS-CoV-2 S-specific T-cell response in pre-COVID-19 healthy donors’ samples. These results could have implications for protective immunity against SARS-CoV-2 and recurrent COVID-19 and may help for the design of new prototypes and boosting vaccine strategies

Combination Therapy With Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors in Older Patients With Type 2 Diabetes: A Real-World Evidence Study

Objectives: Scientific literature about the combination of glucagon-like peptide-1 receptor agonists (GLP1ra) and sodium-glucose cotransporter 2 (SGLT2) inhibitors in older patients is scarce. We sought to assess the real-world efficacy and safety of SGLT2 inhibitors and GLP-1ra combination therapy in older patients (>65 years of age). Methods: This was an observational, prospective, multicenter study based on clinical practice. Patients were stratified according to tertiles of baseline glycated hemoglobin (A1C) levels and to treatment schedule. Results: We included 113 patients (65.5% men, mean age 70.4±8.8 years). The body mass index was 36.5 (±6.6) kg/m2. The baseline A1C level was 8.0% (±1.2%). At the 6-month follow up, we found a significant reduction in A1C levels (–1.1%; p<0.0001), body mass index (–2.1 kg/m2; p<0.00003) and systolic blood pressure (–13 mmHg; p<0.000005). Patients who had the highest baseline A1C levels (≥8.4%) showed greater improvement in A1C levels (p<0.0001), weight (p<0.0001) and quality-of-life scores (p<0.0001). The greatest reduction in A1C levels and weight was seen in patients who started both drugs simultaneously (p<0.0001). The second greatest reduction was seen when GLP-1ra was added to previous treatment with an SGLT2i (p<0.0001). Also of note was a decrease in systolic blood pressure in patients for whom an SGLT2i was added to previous GLP-1ra treatment (p<0.0001). Of the patients, 34.3% achieved the combined endpoint of A1C levels <7% and weight loss ≥5% without hypoglycemia. Conclusions: This study’s findings provide evidence of clinically meaningful reductions in A1C level, body weight and systolic blood pressure in older patients with type 2 diabetes who are taking combined regimens. The dropout and hypoglycemia rates were minimal, and treatment was tolerated well

Structure of the Helicase Domain of DNA Polymerase Theta Reveals a Possible Role in the Microhomology-Mediated End-Joining Pathway

DNA polymerase theta (Polθ) has been identified as a crucial alternative non-homologous end-joining factor in mammalian cells. Polθ is upregulated in a range of cancer cell types defective in homologous recombination, and knockdown has been shown to inhibit cell survival in a subset of these, making it an attractive target for cancer treatment. We present crystal structures of the helicase domain of human Polθ in the presence and absence of bound nucleotides, and a characterization of its DNA-binding and DNA-stimulated ATPase activities. Comparisons with related helicases from the Hel308 family identify several unique features. Polθ exists as a tetramer both in the crystals and in solution. We propose a model for DNA binding to the Polθ helicase domain in the context of the Polθ tetramer, which suggests a role for the helicase domain in strand annealing of DNA templates for subsequent processing by the polymerase domain

Early biomarkers of diabetic kidney disease. A focus on albuminuria and a new combination of antidiabetic agents

Aims: We aimed to determine the efficacy and safety of sodium-glucose cotransporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists to prevent worsening urinary albumin-to-creatinine ratio as an early biomarker of diabetes kidney disease. Methods: A total of 178 patients with type 2 diabetes and obesity received combination treatment with SGLT2i added to GLP1ra (n = 76), GLP1ra added to SGLT2i (n = 50) or GLP1ra plus SGLT2i from start (n = 52), according to investigators´ best clinical judgement. Major outcomes assessed at 26 weeks were changes in urine albumintocreatinine-ratio (UACR), estimated glomerular filtration rate (eGFR), glycated haemoglobin, body weight and systolic blood pressure. Results: All patients (58.6% men, mean age 61.9 ± 10.0 years) completed the study. Baseline HbA1c, weight and eGFR levels were 8.2 ± 0.9%, 109.9 ± 19 kg and 83.3 ± 19.6 mL/min/m2 , respectively. At 26 weeks, we found significant reductions in HbA1c (1.16%), weight (5.17 kg) and systolic blood pressure (8.13 mmHg). The reduction in UACR was 15.14 mg/g (95% CI 8.50-22.4) (-24.6 ± 64.7%), which was greatest in the group of patients with SGLT2i added on to GLP1ra therapy (116.7 mg/g; 95% CI: 54-296.5 mg/g; P < .001. Patients with urinary albumin-to-creatinine ratio ≥30 mg/g, showed a higher declines (63.18 mg/g [95% CI 44.5-104.99]) (-56 ± 65.9%). The greatest reduction in urinary albumin-to-creatinine ratio was obtained when SGLT2i was added to GLP1ra (116.7 mg/g). The eGFR did not significantly change along the study period. Conclusion: Our results show the beneficial effect of GLP1ra and SGLT2i combination therapy on early biomarkers of diabetes kidney disease such as albuminuria and in other significant outcomes for diabetes control