In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

Leishmaniasis represents a major international health problem, has a high morbidity and mortality rate, and is classified as an emerging and uncontrolled disease by the World Health Organization. The migration of population from endemic to nonendemic areas, and tourist activities in endemic regions are spreading the disease to new areas. Unfortunately, treatment of leishmaniasis is far from satisfactory, with only a few drugs available that show significant side-effects. Here, we show in vitro and in vivo evidence for the antileishmanial activity of the ether phospholipid edelfosine, being effective against a wide number of Leishmania spp. causing cutaneous, mucocutaneous and visceral leishmaniasis. Our experimental mouse and hamster models demonstrated not only a significant antileishmanial activity of edelfosine oral administration against different wild-type Leishmania spp., but also against parasites resistant to pentavalent antimonials, which constitute the first line of treatment worldwide. In addition, edelfosine exerted a higher antileishmanial activity and a lower proneness to generate drug resistance than miltefosine, the first drug against leishmaniasis that can be administered orally. These data, together with our previous findings, showing an anti-inflammatory action and a very low toxicity profile, suggest that edelfosine is a promising orally administered drug for leishmaniasis, thus warranting clinical evaluation

Potential of Core-Collapse Supernova Neutrino Detection at JUNO

JUNO is an underground neutrino observatory under construction in Jiangmen, China. It uses 20kton liquid scintillator as target, which enables it to detect supernova burst neutrinos of a large statistics for the next galactic core-collapse supernova (CCSN) and also pre-supernova neutrinos from the nearby CCSN progenitors. All flavors of supernova burst neutrinos can be detected by JUNO via several interaction channels, including inverse beta decay, elastic scattering on electron and proton, interactions on C12 nuclei, etc. This retains the possibility for JUNO to reconstruct the energy spectra of supernova burst neutrinos of all flavors. The real time monitoring systems based on FPGA and DAQ are under development in JUNO, which allow prompt alert and trigger-less data acquisition of CCSN events. The alert performances of both monitoring systems have been thoroughly studied using simulations. Moreover, once a CCSN is tagged, the system can give fast characterizations, such as directionality and light curve

Detection of the Diffuse Supernova Neutrino Background with JUNO

As an underground multi-purpose neutrino detector with 20 kton liquid scintillator, Jiangmen Underground Neutrino Observatory (JUNO) is competitive with and complementary to the water-Cherenkov detectors on the search for the diffuse supernova neutrino background (DSNB). Typical supernova models predict 2-4 events per year within the optimal observation window in the JUNO detector. The dominant background is from the neutral-current (NC) interaction of atmospheric neutrinos with 12C nuclei, which surpasses the DSNB by more than one order of magnitude. We evaluated the systematic uncertainty of NC background from the spread of a variety of data-driven models and further developed a method to determine NC background within 15\% with {\it{in}} {\it{situ}} measurements after ten years of running. Besides, the NC-like backgrounds can be effectively suppressed by the intrinsic pulse-shape discrimination (PSD) capabilities of liquid scintillators. In this talk, I will present in detail the improvements on NC background uncertainty evaluation, PSD discriminator development, and finally, the potential of DSNB sensitivity in JUNO

Evolutionary and Ecological Causes and Consequences of Trophic Niche Variation in Ursids

Individual variation and fitness are the cornerstones of evolution by natural selection. The trophic niche represents an important source of phenotypic variation on which natural selection can act. Although individual variation is fundamental to species-level ecological and evolutionary change, individual variation is often ignored in population-level approaches to wildlife ecology, conservation and management. Failing to link individual resource use to fitness or to biological outcomes related to fitness limits us to managing for the average resource needs of a population, which may be insufficient for protecting the diversity of resource use within populations and the underlying eco-evolutionary processes that generate that diversity. My goals were to provide insights into the mechanisms that generate and constrain intrapopulation trophic niche variation, evaluate whether linkages exist between individual biological outcomes and variation in food habits across the range of resources consumed within generalist consumer populations and examine how that variation manifests in population-level responses. I investigated the causes and physiological consequences of intrapopulation trophic niche variation in two generalist consumers, the American black bear (Ursus americanus) and brown bear (U. arctos) across three sites in British Columbia, CAN and at one site in Alaska, USA. My primary tools included stable isotope analysis to estimate diet, enzyme-linked immunoassay of hair to quantify the hormone cortisol for indexing physiological stress, and genetic analyses to identify individuals, species, and sex and to estimate ancestry. I found that individual differences in resource use can result in similar biological outcomes and that similar resource use can result in different biological outcomes. Intra- and interspecific competition, sex-based differences in nutritional and social constraints and annual variation in food availability all influenced trophic niche variation and the resultant biological outcomes. I also found evidence of a link between intrapopulation trophic niche variation and population genetic structure. My results highlight the diverse ecological drivers and diverse consequences of trophic niche variation, which further illuminates why the trophic niche is a nexus for eco-evolutionary dynamics

Predictors and outcomes of first pass efficacy in posterior circulation strokes: Insights from STAR collaboration

Background: First-pass efficacy (FPE) has been established as an important predictor of favorable functional outcomes after endovascular thrombectomy (ET) in anterior circulation strokes. In this retrospective cohort study, we investigate predictors and clinical outcomes of FPE in posterior circulation strokes (pcAIS). Methods: The Stroke Thrombectomy and Aneurysm Registry database was used to identify pcAIS patients who achieved FPE. Their baseline characteristics and outcomes were compared with the non-FPE group. The primary outcome was a 90-day modified Rankin Scale (mRS) of 0–3. Univariate (UVA) and multivariate (MVA) analyses were done to evaluate predictors of FPE. Safety outcomes included distal emboli, vessel rupture, symptomatic intracranial hemorrhage, and mortality. Results: Of 359 patients, 179 (50%) achieved FPE. Clot burden, occlusion site, and ET technique-related variables were similar between the two groups except for shorter procedure time with FPE. The primary outcome was significantly better with FPE (56.4% vs. 32.8%, p < 0.001). Complications were similar except for a higher rate of distal emboli in non-FPE group (11.1% vs. 3.2%, p = 0.032). Atrial fibrillation (Afib) had increased odds (aOR: 2.06, 95% CI; 1.24, 3.4, p = 0.005) and prior ischemic stroke had decreased odds (aOR: 0.524, 95% CI; 0.28, 0.97, p = 0.04) of FPE. Afib was the only independent predictor of FPE on MVA (1.94, 95% CI; 1.1, 3.43, p = 0.022). Conclusions: Higher rate of FPE in Afib-related pcAIS could possibly be explained by the differences in clot composition and degree of in-situ atherosclerotic disease burden. Future studies are warranted to explore the relationship of clot composition with ET outcomes