Ensemble evaluation of hydrological model hypotheses

It is demonstrated for the first time how model parameter, structural and data uncertainties can be accounted for explicitly and simultaneously within the Generalized Likelihood Uncertainty Estimation (GLUE) methodology. As an example application, 72 variants of a single soil moisture accounting store are tested as simplified hypotheses of runoff generation at six experimental grassland field-scale lysimeters through model rejection and a novel diagnostic scheme. The fields, designed as replicates, exhibit different hydrological behaviors which yield different model performances. For fields with low initial discharge levels at the beginning of events, the conceptual stores considered reach their limit of applicability. Conversely, one of the fields yielding more discharge than the others, but having larger data gaps, allows for greater flexibility in the choice of model structures. As a model learning exercise, the study points to a “leaking” of the fields not evident from previous field experiments. It is discussed how understanding observational uncertainties and incorporating these into model diagnostics can help appreciate the scale of model structural error

Teacher agency in curriculum making: agents of change and spaces for manoeuvre

In the wake of new forms of curricular policy in many parts of the world, teachers are increasingly required to act as agents of change. And yet, teacher agency is under-theorised and often misconstrued in the educational change literature, wherein agency and change are seen as synonymous and positive. This paper addresses the issue of teacher agency in the context of an empirical study of curriculum making in schooling. Drawing upon the existing literature, we outline an ecological view of agency as an effect. These insights frame the analysis of a set of empirical data, derived from a research project about curriculum-making in a school and further education college in Scotland. Based upon the evidence, we argue that the extent to which teachers are able to achieve agency varies from context to context based upon certain environmental conditions of possibility and constraint, and that an important factor in this lies in the beliefs, values and attributes that teachers mobilise in relation to particular situations

Albendazole and antibiotics synergize to deliver short-course anti-Wolbachiacurative treatments in preclinical models of filariasis

Elimination of filariasis requires a macrofilaricide treatment that can be delivered within a 7-day period. Here we have identified a synergy between the anthelmintic albendazole (ABZ) and drugs depleting the filarial endosymbiont Wolbachia, a proven macrofilaricide target, which reduces treatment from several weeks to 7 days in preclinical models. ABZ had negligible effects on Wolbachia but synergized with minocycline or rifampicin (RIF) to deplete symbionts, block embryogenesis, and stop microfilariae production. Greater than 99% Wolbachia depletion following 7-day combination of RIF+ABZ also led to accelerated macrofilaricidal activity. Thus, we provide preclinical proof-of-concept of treatment shortening using antibiotic+ABZ combinations to deliver anti-Wolbachia sterilizing and macrofilaricidal effects. Our data are of immediate public health importance as RIF+ABZ are registered drugs and thus immediately implementable to deliver a 1-wk macrofilaricide. They also suggest that novel, more potent anti-Wolbachia drugs under development may be capable of delivering further treatment shortening, to days rather than weeks, if combined with benzimidazoles

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

A JWST survey of the supernova remnant Cassiopeia A

We present initial results from a James Webb Space Telescope (JWST) survey of the youngest Galactic core-collapse supernova remnant, Cassiopeia A (Cas A), made up of NIRCam and MIRI imaging mosaics that map emission from the main shell, interior, and surrounding circumstellar/interstellar material (CSM/ISM). We also present four exploratory positions of MIRI Medium Resolution Spectrograph integral field unit spectroscopy that sample ejecta, CSM, and associated dust from representative shocked and unshocked regions. Surprising discoveries include (1) a weblike network of unshocked ejecta filaments resolved to ∼0.01 pc scales exhibiting an overall morphology consistent with turbulent mixing of cool, low-entropy matter from the progenitor’s oxygen layer with hot, high-entropy matter heated by neutrino interactions and radioactivity; (2) a thick sheet of dust-dominated emission from shocked CSM seen in projection toward the remnant’s interior pockmarked with small (∼1″) round holes formed by ≲0.″1 knots of high-velocity ejecta that have pierced through the CSM and driven expanding tangential shocks; and (3) dozens of light echoes with angular sizes between ∼0.″1 and 1′ reflecting previously unseen fine-scale structure in the ISM. NIRCam observations place new upper limits on infrared emission (≲20 nJy at 3 μm) from the neutron star in Cas A’s center and tightly constrain scenarios involving a possible fallback disk. These JWST survey data and initial findings help address unresolved questions about massive star explosions that have broad implications for the formation and evolution of stellar populations, the metal and dust enrichment of galaxies, and the origin of compact remnant objects

Efficacy of Major Plant Extracts/Molecules on Field Insect Pests

Insect pests are considered the major hurdle in enhancing the production and productivity of any farming system. The use of conventional synthetic pesticides has led to the emergence of pesticide-resistant insects, environmental pollution, and negative effects on natural enemies, which have caused an ecological imbalance of the predator-prey ratio and human health hazards; therefore, eco-friendly alternative strategies are required. The plant kingdom, a rich repertoire of secondary metabolites, can be tapped as an alternative for insect pest management strategies. A number of plants have been documented to have insecticidal properties against various orders of insects in vitro by acting as antifeedants, repellents, sterilant and oviposition deterrents, etc. However, only a few plant compounds are applicable at the field level or presently commercialised. Here, we have provided an overview of the broad-spectrum insecticidal activity of plant compounds from neem, Annona, Pongamia, and Jatropha. Additionally, the impact of medicinal plants, herbs, spices, and essential oils has been reviewed briefl

A potential role for cannabinoid receptors in the therapeutic action of fenofibrate

Cannabinoids are reported to have actions through peroxisome proliferator-activated receptors (PPARs), which led us to investigate PPAR agonists for activity at the cannabinoid receptors. Radio-ligand binding and functional assays were conducted using human recombinant cannabinoid type 1 (CB1) or cannabinoid type 2 (CB2) receptors, as well as the guinea pig isolated ileum, using the full agonist CP55940 as a positive control. The PPAR-alpha agonist fenofibrate exhibited submicromolar affinity for both receptors (pKi CB1, 6.3 +/- 0.1; CB2, 7.7 +/- 0.1). Functionally, fenofibrate acted as an agonist at the CB2 receptor (pEC50, 7.7 +/- 0.1) and a partial agonist at the CB1 receptor, although with a decrease in functional response at higher concentrations, producing bell-shaped concentration-response curves. High concentrations of fenofibrate were able to increase the dissociation rate constant for [(3)H]-CP55940 at the CB1 receptor, (kfast without: 1.2 +/- 0.2/min; with: 3.8 +/- 0.1 x 10(-2)/min) and decrease the maximal response to CP55940 (Rmax, 86 +/- 2%), which is consistent with a negative allosteric modulator. Fenofibrate also reduced electrically induced contractions in isolated guinea pig ileum via CB1 receptors (pEC50, 6.0 +/- 0.4). Fenofibrate is thus identified as an example of a new class of cannabinoid receptor ligand and allosteric modulator, with the potential to interact therapeutically with cannabinoid receptors in addition to its primary PPAR target