Assessment of the onset of action of afoxolaner against existing adult flea (Ctenocephalides felis) infestations on dogs

AbstractThe speed of kill of afoxolaner against experimental infestations by Ctenocephalides felis was evaluated after oral administration of afoxolaner in a soft chew (NEXGARD®) at a dose to achieve 2.5mg/kg bodyweight. Forty beagles were allocated to two treatment groups. Dogs in Treatment Group 1 were untreated controls. Dogs in Treatment Group 2 were treated on Day-0 with afoxolaner, according to their pre-treatment bodyweight. All dogs were infested with approximately 100 C. felis on Day-1. Live fleas were counted upon removal at 5 time points after treatment (i.e., 2, 4, 8, 12 and 24h after treatment). For each time point, counts were performed on 4 dogs from each of the treated and the untreated groups. Early curative flea killing efficacy was evaluated with respect to the untreated control group. The afoxolaner treated group had significantly fewer fleas than the untreated control group at 8, 12, and 24h (p<0.001). The percent efficacies of orally administered afoxolaner were 15.0%, 87.8%, 99.5%, 100.0%, and 100.0% at 2, 4, 8, 12, and 24h, respectively. In this study, afoxolaner began killing fleas by 2h after treatment with increasing efficacy at subsequent time points and had >99.5% efficacy at 8, 12, and 24h after treatment demonstrating an early onset of action

Metabarcoding and metabolome analyses of copepod grazing reveal feeding preference and linkage to metabolite classes in dynamic microbial plankton communities

In order to characterize copepod feeding in relation to microbial plankton community dynamics, we combined metabarcoding and metabolome analyses during a 22-day seawater mesocosm experiment. Nutrient amendment of mesocosms promoted the development of haptophyte (Phaeocystis pouchetii)- and diatom (Skeletonema marinoi)-dominated plankton communities in mesocosms, in which Calanus sp. copepods were incubated for 24 h in flow-through chambers to allow access to prey particles (<500 μm). Copepods and mesocosm water sampled six times spanning the experiment were analysed using metabarcoding, while intracellular metabolite profiles of mesocosm plankton communities were generated for all experimental days. Taxon-specific metabarcoding ratios (ratio of consumed prey to available prey in the surrounding seawater) revealed diverse and dynamic copepod feeding selection, with positive selection on large diatoms, heterotrophic nanoflagellates and fungi, while smaller phytoplankton, including P. pouchetii, were passively consumed or even negatively selected according to our indicator. Our analysis of the relationship between Calanus grazing ratios and intracellular metabolite profiles indicates the importance of carbohydrates and lipids in plankton succession and copepod–prey interactions. This molecular characterization of Calanus sp. grazing therefore provides new evidence for selective feeding in mixed plankton assemblages and corroborates previous findings that copepod grazing may be coupled to the developmental and metabolic stage of the entire prey community rather than to individual prey abundances

Human Recombinant Alkaline Phosphatase (Ilofotase Alfa) Protects Against Kidney Ischemia-Reperfusion Injury in Mice and Rats Through Adenosine Receptors

Adenosine triphosphate (ATP) released from injured or dying cells is a potent pro-inflammatory “danger” signal. Alkaline phosphatase (AP), an endogenous enzyme that de-phosphorylates extracellular ATP, likely plays an anti-inflammatory role in immune responses. We hypothesized that ilofotase alfa, a human recombinant AP, protects kidneys from ischemia-reperfusion injury (IRI), a model of acute kidney injury (AKI), by metabolizing extracellular ATP to adenosine, which is known to activate adenosine receptors. Ilofotase alfa (iv) with or without ZM241,385 (sc), a selective adenosine A2A receptor (A2AR) antagonist, was administered 1 h before bilateral IRI in WT, A2AR KO (Adora2a–/–) or CD73–/– mice. In additional studies recombinant alkaline phosphatase was given after IRI. In an AKI-on-chronic kidney disease (CKD) ischemic rat model, ilofotase alfa was given after the three instances of IRI and rats were followed for 56 days. Ilofotase alfa in a dose dependent manner decreased IRI in WT mice, an effect prevented by ZM241,385 and partially prevented in Adora2a–/– mice. Enzymatically inactive ilofotase alfa was not protective. Ilofotase alfa rescued CD73–/– mice, which lack a 5′-ectonucleotidase that dephosphorylates AMP to adenosine; ZM241,385 inhibited that protection. In both rats and mice ilofotase alfa ameliorated IRI when administered after injury, thus providing relevance for therapeutic dosing of ilofotase alfa following established AKI. In an AKI-on-CKD ischemic rat model, ilofotase alfa given after the third instance of IRI reduced injury. These results suggest that ilofotase alfa promotes production of adenosine from liberated ATP in injured kidney tissue, thereby amplifying endogenous mechanisms that can reverse tissue injury, in part through A2AR-and non-A2AR-dependent signaling pathways

Student public commitment in a school-based diabetes prevention project: impact on physical health and health behavior

<p>Abstract</p> <p>Background</p> <p>As concern about youth obesity continues to mount, there is increasing consideration of widespread policy changes to support improved nutritional and enhanced physical activity offerings in schools. A critical element in the success of such programs may be to involve students as spokespeople for the program. Making such a public commitment to healthy lifestyle program targets (improved nutrition and enhanced physical activity) may potentiate healthy behavior changes among such students and provide a model for their peers. This paper examines whether student's "public commitment"--voluntary participation as a peer communicator or in student-generated media opportunities--in a school-based intervention to prevent diabetes and reduce obesity predicted improved study outcomes including reduced obesity and improved health behaviors.</p> <p>Methods</p> <p>Secondary analysis of data from a 3-year randomized controlled trial conducted in 42 middle schools examining the impact of a multi-component school-based program on body mass index (BMI) and student health behaviors. A total of 4603 students were assessed at the beginning of sixth grade and the end of eighth grade. Process evaluation data were collected throughout the course of the intervention. All analyses were adjusted for students' baseline values. For this paper, the students in the schools randomized to receive the intervention were further divided into two groups: those who participated in public commitment activities and those who did not. Students from comparable schools randomized to the assessment condition constituted the control group.</p> <p>Results</p> <p>We found a lower percentage of obesity (greater than or equal to the 95^thpercentile for BMI) at the end of the study among the group participating in public commitment activities compared to the control group (21.5% vs. 26.6%, p = 0.02). The difference in obesity rates at the end of the study was even greater among the subgroup of students who were overweight or obese at baseline; 44.6% for the "public commitment" group, versus 53.2% for the control group (p = 0.01). There was no difference in obesity rates between the group not participating in public commitment activities and the control group (26.4% vs. 26.6%).</p> <p>Conclusions</p> <p>Participating in public commitment activities during the HEALTHY study may have potentiated the changes promoted by the behavioral, nutrition, and physical activity intervention components.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov number, <a href="http://www.clinicaltrials.gov/ct2/show/NCT00458029">NCT00458029</a></p

The wide-field, multiplexed, spectroscopic facility WEAVE : survey design, overview, and simulated implementation

Funding for the WEAVE facility has been provided by UKRI STFC, the University of Oxford, NOVA, NWO, Instituto de Astrofísica de Canarias (IAC), the Isaac Newton Group partners (STFC, NWO, and Spain, led by the IAC), INAF, CNRS-INSU, the Observatoire de Paris, Région Île-de-France, CONCYT through INAOE, Konkoly Observatory (CSFK), Max-Planck-Institut für Astronomie (MPIA Heidelberg), Lund University, the Leibniz Institute for Astrophysics Potsdam (AIP), the Swedish Research Council, the European Commission, and the University of Pennsylvania.WEAVE, the new wide-field, massively multiplexed spectroscopic survey facility for the William Herschel Telescope, will see first light in late 2022. WEAVE comprises a new 2-degree field-of-view prime-focus corrector system, a nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini' integral field units (IFUs), and a single large IFU. These fibre systems feed a dual-beam spectrograph covering the wavelength range 366-959 nm at R ∼ 5000, or two shorter ranges at R ∼ 20,000. After summarising the design and implementation of WEAVE and its data systems, we present the organisation, science drivers and design of a five- to seven-year programme of eight individual surveys to: (i) study our Galaxy's origins by completing Gaia's phase-space information, providing metallicities to its limiting magnitude for ∼ 3 million stars and detailed abundances for ∼ 1.5 million brighter field and open-cluster stars; (ii) survey ∼ 0.4 million Galactic-plane OBA stars, young stellar objects and nearby gas to understand the evolution of young stars and their environments; (iii) perform an extensive spectral survey of white dwarfs; (iv) survey  ∼ 400 neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and kinematics of stellar populations and ionised gas in z 1 million spectra of LOFAR-selected radio sources; (viii) trace structures using intergalactic/circumgalactic gas at z > 2. Finally, we describe the WEAVE Operational Rehearsals using the WEAVE Simulator.PostprintPeer reviewe

The wide-field, multiplexed, spectroscopic facility WEAVE: Survey design, overview, and simulated implementation

WEAVE, the new wide-field, massively multiplexed spectroscopic survey facility for the William Herschel Telescope, will see first light in late 2022. WEAVE comprises a new 2-degree field-of-view prime-focus corrector system, a nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini' integral field units (IFUs), and a single large IFU. These fibre systems feed a dual-beam spectrograph covering the wavelength range 366$-$959\,nm at $R\sim5000$, or two shorter ranges at $R\sim20\,000$. After summarising the design and implementation of WEAVE and its data systems, we present the organisation, science drivers and design of a five- to seven-year programme of eight individual surveys to: (i) study our Galaxy's origins by completing Gaia's phase-space information, providing metallicities to its limiting magnitude for $\sim$3 million stars and detailed abundances for $\sim1.5$ million brighter field and open-cluster stars; (ii) survey $\sim0.4$ million Galactic-plane OBA stars, young stellar objects and nearby gas to understand the evolution of young stars and their environments; (iii) perform an extensive spectral survey of white dwarfs; (iv) survey $\sim400$ neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and kinematics of stellar populations and ionised gas in $z<0.5$ cluster galaxies; (vi) survey stellar populations and kinematics in $\sim25\,000$ field galaxies at $0.3\lesssim z \lesssim 0.7$; (vii) study the cosmic evolution of accretion and star formation using $>1$ million spectra of LOFAR-selected radio sources; (viii) trace structures using intergalactic/circumgalactic gas at $z>2$. Finally, we describe the WEAVE Operational Rehearsals using the WEAVE Simulator.Comment: 41 pages, 27 figures, accepted for publication by MNRA

The Anorexia Nervosa Genetics Initiative (ANGI): overview and methods

This manuscript version is made available under the CC-BY-NC-ND 4.0 license: http://creativecommons.org/licenses/by-nc-nd/4.0/ which permits use, distribution and reproduction in any medium, provided the original work is properly cited. This author accepted manuscript is made available following 12 month embargo from date of publication (October 2018) in accordance with the publisher’s archiving policyBackground Genetic factors contribute to anorexia nervosa (AN); and the first genome-wide significant locus has been identified. We describe methods and procedures for the Anorexia Nervosa Genetics Initiative (ANGI), an international collaboration designed to rapidly recruit 13,000 individuals with AN and ancestrally matched controls. We present sample characteristics and the utility of an online eating disorder diagnostic questionnaire suitable for large-scale genetic and population research. Methods ANGI recruited from the United States (US), Australia/New Zealand (ANZ), Sweden (SE), and Denmark (DK). Recruitment was via national registers (SE, DK); treatment centers (US, ANZ, SE, DK); and social and traditional media (US, ANZ, SE). All cases had a lifetime AN diagnosis based on DSM-IV or ICD-10 criteria (excluding amenorrhea). Recruited controls had no lifetime history of disordered eating behaviors. To assess the positive and negative predictive validity of the online eating disorder questionnaire (ED100K-v1), 109 women also completed the Structured Clinical Interview for DSM-IV (SCID), Module H. Results Blood samples and clinical information were collected from 13,363 individuals with lifetime AN and from controls. Online diagnostic phenotyping was effective and efficient; the validity of the questionnaire was acceptable. Conclusions Our multi-pronged recruitment approach was highly effective for rapid recruitment and can be used as a model for efforts by other groups. High online presence of individuals with AN rendered the Internet/social media a remarkably effective recruitment tool in some countries. ANGI has substantially augmented Psychiatric Genomics Consortium AN sample collection.Please refer to published article

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p