Antibiotic-induced release of small extracellular vesicles (exosomes) with surface-associated DNA

Recently, biological roles of extracellular vesicles (which include among others exosomes, microvesicles and apoptotic bodies) have attracted substantial attention in various fields of biomedicine. Here we investigated the impact of sustained exposure of cells to the fluoroquinolone antibiotic ciprofloxacin on the released extracellular vesicles. Ciprofloxacin is widely used in humans against bacterial infections as well as in cell cultures against Mycoplasma contamination. However, ciprofloxacin is an inducer of oxidative stress and mitochondrial dysfunction of mammalian cells. Unexpectedly, here we found that ciprofloxacin induced the release of both DNA (mitochondrial and chromosomal sequences) and DNA-binding proteins on the exofacial surfaces of small extracellular vesicles referred to in this paper as exosomes. Furthermore, a label-free optical biosensor analysis revealed DNA-dependent binding of exosomes to fibronectin. DNA release on the surface of exosomes was not affected any further by cellular activation or apoptosis induction. Our results reveal for the first time that prolonged low-dose ciprofloxacin exposure leads to the release of DNA associated with the external surface of exosomes

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

HTAP3 fires: towards a multi-model, multi-pollutant study of fire impacts

Open biomass burning has major impacts globally and regionally on atmospheric composition. Fire emissions include particulate matter, tropospheric ozone precursors, greenhouse gases, as well as persistent organic pollutants, mercury and other metals. Fire frequency, intensity, duration, and location are changing as the climate warms, and modelling these fires and their impacts is becoming more and more critical to inform climate adaptation and mitigation, as well as land management. Indeed, the air pollution from fires can reverse the progress made by emission controls on industry and transportation. At the same time, nearly all aspects of fire modelling – such as emissions, plume injection height, long-range transport, and plume chemistry – are highly uncertain. This paper outlines a multi-model, multi-pollutant, multi-regional study to improve the understanding of the uncertainties and variability in fire atmospheric science, models, and fires’ impacts, in addition to providing quantitative estimates of the air pollution and radiative impacts of biomass burning. Coordinated under the auspices of the Task Force on Hemispheric Transport of Air Pollution, the international atmospheric modelling and fire science communities are working towards the common goal of improving global fire modelling and using this multi-model experiment to provide estimates of fire pollution for impact studies. This paper outlines the research needs, opportunities, and options for the fire-focused multi-model experiments and provides guidance for these modelling experiments, outputs, and analysis that are to be pursued over the next 3 to 5 years. It proposes a plan for delivering specific products at key points over this period to meet important milestones relevant to science and policy audiences