Selenium Biotransformations in an Engineered Aquatic Ecosystem for Bioremediation of Agricultural Wastewater via Brine Shrimp Production

An engineered aquatic ecosystem was specifically designed to bioremediate selenium (Se), occurring as oxidized inorganic selenate from hypersalinized agricultural drainage water while producing brine shrimp enriched in organic Se and omega-3 and omega-6 fatty acids for use in value added nutraceutical food supplements. Selenate was successfully bioremediated by microalgal metabolism into organic Se (seleno-amino acids) and partially removed via gaseous volatile Se formation. Furthermore, filterfeeding brine shrimp that accumulated this organic Se were removed by net harvest. Thriving in this engineered pond system, brine shrimp (Artemia franciscana Kellogg) and brine fly (Ephydridae sp.) have major ecological relevance as important food sources for large populations of waterfowl, breeding, and migratory shore birds. This aquatic ecosystem was an ideal model for study because it mimics trophic interactions in a Se polluted wetland. Inorganic selenate in drainage water was metabolized differently in microalgae, bacteria, and diatoms where it was accumulated and reduced into various inorganic forms (selenite, selenide, or elemental Se) or partially incorporated into organic Se mainly as selenomethionine. Brine shrimp and brine fly larva then bioaccumulated Se from ingesting aquatic microorganisms and further metabolized Se predominately into organic Se forms. Importantly, adult brine flies, which hatched from aquatic larva, bioaccumulated the highest Se concentrations of all organisms tested

High speed solid rotor permanent magnet machines: concept and design

This paper proposes a novel solid rotor topology for an Interior Permanent Magnet (IPM) machine, adopted in this case for an aircraft starter-generator design. The key challenge in the design is to satisfy two operating conditions which are: a high torque at start and a high speed at cruise. Conventional IPM topologies which are highly capable of extended field weakening are found to be limited at high speed due to structural constraints associated with the rotor material. To adopt the IPM concept for high speed operation, it is proposed to adopt a rotor constructed from semi-magnetic stainless steel, which has a higher yield strength than laminated silicon steel. To maintain minimal stress levels and also minimize the resultant eddy current losses due to the lack of laminations, different approaches are considered and studied. Finally, to achieve a better tradeoff between the structural and electromagnetic constraints, a novel slitted approach is implemented on the rotor. The proposed rotor topology is verified using electromagnetic, static structural and dynamic structural Finite Element (FE) analyses. An experiment is performed to confirm the feasibility of the proposed rotor. It is shown that the proposed solid rotor concept for an IPM fulfils the design requirements whilst satisfying the structural, thermal and magnetic limitations

Three-Dimensional Double-Ridge Internal Tide Resonance in Luzon Strait

The three-dimensional (3D) double-ridge internal tide interference in the Luzon Strait in the South China Sea is examined by comparing 3D and two-dimensional (2D) realistic simulations. Both the 3D simulations and observations indicate the presence of 3D first-mode (semi)diurnal standing waves in the 3.6-km-deep trench in the strait. As in an earlier 2D study, barotropic-to-baroclinic energy conversion, flux divergence, and dissipation are greatly enhanced when semidiurnal tides dominate relative to periods dominated by diurnal tides. The resonance in the 3D simulation is several times stronger than in the 2D simulations for the central strait. Idealized experiments indicate that, in addition to ridge height, the resonance is only a function of separation distance and not of the along-ridge length; that is, the enhanced resonance in 3D is not caused by 3D standing waves or basin modes. Instead, the difference in resonance between the 2D and 3D simulations is attributed to the topographic blocking of the barotropic flow by the 3D ridges, affecting wave generation, and a more constructive phasing between the remotely generated internal waves, arriving under oblique angles, and the barotropic tide. Most of the resonance occurs for the first mode. The contribution of the higher modes is reduced because of 3D radiation, multiple generation sites, scattering, and a rapid decay in amplitude away from the ridge

Locus Coeruleus tracking of prediction errors optimises cognitive flexibility:An Active Inference model

<div><p>The locus coeruleus (LC) in the pons is the major source of noradrenaline (NA) in the brain. Two modes of LC firing have been associated with distinct cognitive states: changes in tonic rates of firing are correlated with global levels of arousal and behavioural flexibility, whilst phasic LC responses are evoked by salient stimuli. Here, we unify these two modes of firing by modelling the response of the LC as a correlate of a prediction error when inferring states for action planning under Active Inference (AI). We simulate a classic Go/No-go reward learning task and a three-arm ‘explore/exploit’ task and show that, if LC activity is considered to reflect the magnitude of high level ‘state-action’ prediction errors, then both tonic and phasic modes of firing are emergent features of belief updating. We also demonstrate that when contingencies change, AI agents can update their internal models more quickly by feeding back this state-action prediction error–reflected in LC firing and noradrenaline release–to optimise learning rate, enabling large adjustments over short timescales. We propose that such prediction errors are mediated by cortico-LC connections, whilst ascending input from LC to cortex modulates belief updating in anterior cingulate cortex (ACC). In short, we characterise the LC/ NA system within a general theory of brain function. In doing so, we show that contrasting, behaviour-dependent firing patterns are an emergent property of the LC that translates state-action prediction errors into an optimal balance between plasticity and stability.</p></div

Murine factor H co-produced in yeast with protein disulfide isomerase ameliorated C3 dysregulation in factor H-Deficient mice

Recombinant human factor H (hFH) has potential for treating diseases linked to aberrant complement regulation including C3 glomerulopathy (C3G) and dry age-related macular degeneration. Murine FH (mFH), produced in the same host, is useful for pre-clinical investigations in mouse models of disease. An abundance of FH in plasma suggests high doses, and hence microbial production, will be needed. Previously, Pichia pastoris produced useful but modest quantities of hFH. Herein, a similar strategy yielded miniscule quantities of mFH. Since FH has 40 disulfide bonds, we created a P. pastoris strain containing a methanol-inducible codon-modified gene for protein-disulfide isomerase (PDI) and transformed this with codon-modified DNA encoding mFH under the same promoter. What had been barely detectable yields of mFH became multiple 10s of mg/L. Our PDI-overexpressing strain also boosted hFH overproduction, by about tenfold. These enhancements exceeded PDI-related production gains reported for other proteins, all of which contain fewer disulfide-stabilized domains. We optimized fermentation conditions, purified recombinant mFH, enzymatically trimmed down its (non-human) N-glycans, characterised its functions in vitro and administered it to mice. In FH-knockout mice, our de-glycosylated recombinant mFH had a shorter half-life and induced more anti-mFH antibodies than mouse serum-derived, natively glycosylated, mFH. Even sequential daily injections of recombinant mFH failed to restore wild-type levels of FH and C3 in mouse plasma beyond 24 hours after the first injection. Nevertheless, mFH functionality appeared to persist in the glomerular basement membrane because C3-fragment deposition here, a hallmark of C3G, remained significantly reduced throughout and beyond the ten-day dosing regimen

Most viral peptides displayed by class I MHC on infected cells are immunogenic

CD8+ T cells are essential effectors in antiviral immunity, recognizing short virus-derived peptides presented by MHC class I (pMHCI) on the surface of infected cells. However, the fraction of viral pMHCI on infected cells that are immunogenic has not been shown for any virus. To approach this fundamental question, we used peptide sequencing by high-resolution mass spectrometry to identify more than 170 vaccinia virus pMHCI presented on infected mouse cells. Next, we screened each peptide for immunogenicity in multiple virus-infected mice, revealing a wide range of immunogenicities. A surprisingly high fraction (>80%) of pMHCI were immunogenic in at least one infected mouse, and nearly 40% were immunogenic across more than half of the mice screened. The high number of peptides found to be immunogenic and the distribution of responses across mice give us insight into the specificity of antiviral CD8+ T cell responses.This work was supported by a Project Grant from the National Health and Medical Research Council Australia (NHMRC) (APP1084283) (to D.C.T., A.W.P., and N.P.C.); an NHMRC Senior Research Fellowship (APP1104329) (to D.C.T.); an NHMRC Principal Research Fellowship (APP1137739) (to A.W.P.); and a Viertel Fellowship, ARC Future Fellowship, and NHMRC Program Grant (APP1071916) (to N.L.L.G.)

REFINE (reduced frequency ImmuNE checkpoint inhibition in cancers): A multi-arm phase II basket trial testing reduced intensity immunotherapy across different cancers

Background Immune checkpoint inhibitors (ICI) have revolutionised treating advanced cancers. ICI are administered intravenously every 2–6 weeks for up to 2 years, until cancer progression/unacceptable toxicity. Physiological efficacy is observed at lower doses than those used as standard of care (SOC). Pharmacodynamic studies indicate sustained target occupancy, despite a pharmacological half-life of 2–3 weeks. Reducing frequency of administration may be possible without compromising outcomes. The REFINE trial aims to limit individual patient exposure to ICI whilst maintaining efficacy, with potential benefits in quality of life and reduced drug treatment/attendance costs. Methods/Design REFINE is a randomised phase II, multi-arm, multi-stage (MAMS) adaptive basket trial investigating extended interval administration of ICIs. Eligible patients are those responding to conventionally dosed ICI at 12 weeks. In stage I, patients (n = 160 per tumour-specific cohort) will be randomly allocated (1:1) to receive maintenance ICI at SOC vs extended dose interval. REFINE is currently recruiting UK patients with locally advanced or metastatic renal cell carcinoma (RCC) who have tolerated and responded to initial nivolumab/ipilimumab, randomised to receive maintenance nivolumab SOC (480 mg 4 weekly) vs extended interval (480 mg 8 weekly). Additional tumour cohorts are planned. Subject to satisfactory outcomes (progression-free survival) stage II will investigate up to 5 different treatment intervals. Secondary outcome measures include overall survival, quality-of-life, treatment-related toxicity, mean incremental pathway costs and quality-adjusted life-years per patient. REFINE is funded by the Jon Moulton Charity Trust and Medical Research Council, sponsored by University College London (UCL), and coordinated by the MRC CTU at UCL