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COVID-19 severity is associated with its respiratory manifestations. Neutralising antibodies against SARS-CoV-2 administered systemically have shown clinical efficacy. However, immediate and direct delivery of neutralising antibodies via inhalation might provide additional respiratory clinical benefits. IBIO123 is a cocktail of three, fully human, neutralising monoclonal antibodies against SARS-CoV-2. We aimed to assess the safety and efficacy of inhaled IBIO123 in individuals with mild-to-moderate COVID-19. This double-blind, dose-ascending, placebo-controlled, first-in-human, phase 1/2 trial recruited symptomatic and non-hospitalised participants with COVID-19 in South Africa and Brazil across 11 centres. Eligible participants were adult outpatients (aged ≥18 years; men and non-pregnant women) infected with COVID-19 (first PCR-confirmed within 72 h) and with mild-to-moderate symptoms, the onset of which had to be within 10 days of randomisation. Using permuted blocks of four, stratified by site, we randomly assigned participants (1:3) to receive single-dose placebo or IBIO123 (1 mg, 5 mg, or 10 mg) in phase 1, and single-dose placebo or IBIO123 (10 mg) in phase 2, in addition to local standard of care. Participants underwent serological testing to identify antibodies against SARS-CoV-2. Participants, investigators, and the study team were masked to treatment assignment. In phase 1, the primary outcome was the safety assessment in the safety population (ie, all participants who received an intervention). In phase 2, the primary outcome was the mean absolute change from baseline to day 5 in SARS-CoV-2 viral load measured by nasopharyngeal swabs analysed using a mixed model for repeated measures in the full analysis set (FAS; ie, participants with one analysable viral load value at baseline and at least one analysable viral load value at day 3 or day 5). Secondary clinical outcomes included safety from baseline to day 29, assessed by evaluating adverse events; the effect of IBIO123 on baseline COVID-19 symptoms resolution until day 6, with symptoms systemically evaluated by the investigators; and disease progression as measured by the COVID-19 WHO Clinical Progression Scale. For clinical endpoints in phase 2, we used a modified FAS (ie, participants who had at least one analysable viral load value over the course of the study, confirming that they were infected with SARS-CoV-2). This trial is now completed and is registered with ClinicalTrials.gov , NCT05298813. Between Dec 4, 2021, and May 23, 2022, 24 participants were enrolled in phase 1. Between July 20, 2022, and Jan 4, 2023, 138 participants were enrolled in phase 2 and five were excluded because they did not meet the inclusion criteria. Participants were randomly assigned to receive IBIO123 (n=18) or placebo (n=6) in phase 1, and randomly assigned to receive IBIO123 (n=104) or placebo (n=34) in phase 2. In phase 2, the study was stopped before reaching the planned accrual because of a decline in COVID-19 incidence. In phase 1, no safety issues were observed. In phase 2, the difference in mean absolute change from baseline viral load to day 5 between participants in the IBIO123 group and participants in the placebo group was –0·29 log 10 copies per mL (95% CI −1·32 to 0·75; p=0·45) in the FAS population and –0·49 log 10 copies per mL (−1·56 to 0·58; p=0·20) in seropositive participants. In the modified FAS, 81 (69%) of 118 participants were at high risk of severe disease progression. The number of participants with resolution of respiratory symptoms at day 6 was 34 (42%) of 81 in the IBIO123 group versus five (17%) of 29 in the placebo group (p=0·017) in the modified FAS population and 19 (35%) of 55 versus three (14%) of 21 among participants at high risk (p=0·083). One participant died and one participant was hospitalised in the placebo group, whereas no deaths or hospitalisations were reported in the IBIO123 group. 39 (38%) of 104 participants in the IBIO123 group had adverse events, compared with 13 (38%) of 34 in the placebo group. Inhalation of IBIO123 was safe. Despite the lack of significant reduction of viral load at day 5, treatment with IBIO123 resulted in a higher proportion of participants with complete resolution of respiratory symptoms at day 6. This study supports further clinical research on inhaled monoclonal antibodies in COVID-19 and respiratory diseases in general. Canadian Strategic Innovation Fund and Immune Biosolutions. [ABSTRACT FROM AUTHOR]

Hepatokines are proteins secreted by the liver that impact the functions of the liver and various tissues through autocrine, paracrine, and endocrine signaling. Recently, Tsukushi (TSK) was identified as a new hepatokine that is induced by obesity and cold exposure. It was proposed that TSK controls sympathetic innervation and thermogenesis in brown adipose tissue (BAT) and that loss of TSK protects against diet-induced obesity and improves glucose homeostasis. Here we report the impact of deleting and/or overexpressing TSK on BAT thermogenic capacity, body weight regulation, and glucose homeostasis. We measured the expression of thermogenic genes and markers of BAT innervation and activation in TSK-null and TSK-overexpressing mice. Body weight, body temperature, and parameters of glucose homeostasis were also assessed in the context of TSK loss and overexpression. The loss of TSK did not affect the thermogenic activation of BAT. We found that TSK-null mice were not protected against the development of obesity and did not show improvement in glucose tolerance. The overexpression of TSK also failed to modulate thermogenesis, body weight gain, and glucose homeostasis in mice. TSK is not a significant regulator of BAT thermogenesis and is unlikely to represent an effective target to prevent obesity and improve glucose homeostasis. • Loss of TSK does not affect brown fat thermogenic capacity. • Loss of TSK does not protect mice against the development of obesity. • Loss of TSK does not improve glucose homeostasis. • Overexpression of TSK does not affect thermogenesis, body weight gain and glucose homeostasis. [ABSTRACT FROM AUTHOR]

Objective The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions into distinct protein complexes (mTORC1 and mTORC2) that regulates growth and metabolism. DEP-domain containing mTOR-interacting protein (DEPTOR) is part of these complexes and is known to reduce their activity. Whether DEPTOR loss affects metabolism and organismal growth in vivo has never been tested. Methods We have generated a conditional transgenic mouse allowing the tissue-specific deletion of DEPTOR. This model was crossed with CMV-cre mice or Albumin-cre mice to generate either whole-body or liver-specific DEPTOR knockout (KO) mice. Results Whole-body DEPTOR KO mice are viable, fertile, normal in size, and do not display any gross physical and metabolic abnormalities. To circumvent possible compensatory mechanisms linked to the early and systemic loss of DEPTOR, we have deleted DEPTOR specifically in the liver, a tissue in which DEPTOR protein is expressed and affected in response to mTOR activation. Liver-specific DEPTOR null mice showed a reduction in circulating glucose upon fasting versus control mice. This effect was not associated with change in hepatic gluconeogenesis potential but was linked to a sustained reduction in circulating glucose during insulin tolerance tests. In addition to the reduction in glycemia, liver-specific DEPTOR KO mice had reduced hepatic glycogen content when fasted. We showed that loss of DEPTOR cell-autonomously increased oxidative metabolism in hepatocytes, an effect associated with increased cytochrome c expression but independent of changes in mitochondrial content or in the expression of genes controlling oxidative metabolism. We found that liver-specific DEPTOR KO mice showed sustained mTORC1 activation upon fasting, and that acute treatment with rapamycin was sufficient to normalize glycemia in these mice. Conclusion We propose a model in which hepatic DEPTOR accelerates the inhibition of mTORC1 during the transition to fasting to adjust metabolism to the nutritional status. [ABSTRACT FROM AUTHOR]

Background/Objective The mechanistic target of rapamycin (mTOR) is a serine–threonine kinase that functions into distinct protein complexes (mTORC1 and mTORC2) that regulate energy homeostasis. DEP-domain containing mTOR-interacting protein (DEPTOR) is part of these complexes and is known to dampen mTORC1 function, consequently reducing mTORC1 negative feedbacks and promoting insulin signaling and Akt/PKB activation in several models. Recently, we observed that DEPTOR is expressed in several structures of the brain including the mediobasal hypothalamus (MBH), a region that regulates energy balance. Whether DEPTOR in the MBH plays a functional role in regulating energy balance and hypothalamic insulin signaling has never been tested. Methods We have generated a novel conditional transgenic mouse model based on the Cre-LoxP system allowing targeted overexpression of DEPTOR. Mice overexpressing DEPTOR in the MBH were subjected to a metabolic phenotyping and MBH insulin signaling was evaluated. Results We first report that systemic (brain and periphery) overexpression of DEPTOR prevents high-fat diet-induced obesity, improves glucose metabolism and protects against hepatic steatosis. These phenotypes were associated with a reduction in food intake and feed efficiency and an elevation in oxygen consumption. Strikingly, specific overexpression of DEPTOR in the MBH completely recapitulated these phenotypes. DEPTOR overexpression was associated with an increase in hypothalamic insulin signaling, as illustrated by elevated Akt/PKB activation. Conclusion Altogether, these results support a role for MBH DEPTOR in the regulation of energy balance and metabolism. [ABSTRACT FROM AUTHOR]

Paludification, the accumulation over the mineral soil of poorly decomposed organic matter mainly originating from Sphagnum spp., transforms black spruce ( Picea mariana ) boreal forests into forested peatlands in the prolonged absence of fire, which diminishes forest productivity. High-severity wildfires reset this process by burning the soil organic layer (SOL) and reinitiating forest succession. In contrast, low severity wildfires impact mainly the soil surface and tree layer and do not significantly reduce SOL depth. In the Clay Belt region of eastern Canada, an area prone to paludification, the current forest harvest practice (careful logging around advanced growth [CLAAG]) removes trees but has little impact on the SOL and the understorey vegetation. This is thought to further promote paludification, which consequently reduces forest productivity. Conversely, clearcut (CC) disturbs the SOL and the understorey vegetation, and is thought to favor tree growth. Furthermore, prescribed burning after clearcut (CCPB) is used as a site preparation technique, but may also be used to control paludification as it can burn part of the organic soil layer. Using a retrospective approach, our study examines three hypotheses: compared to CLAAG, CC and CCPB: (1) have positive effects on soil conditions (e.g. decomposition level and pH), (2) reduce Sphagnum spp. and ericaceous shrub cover and (3) result in enhanced black spruce growth. We sampled 22 sites in which we measured SOL characteristics (e.g. depth, decomposition state), understorey vegetation cover and black spruce growth. Compared to CLAAG, CCPB resulted in increased soil decomposition level and higher pH. CCPB also reduced Sphagnum spp. cover but not ericaceous shrub cover. Black spruce growth rate was higher following CCPB than CC, and mean dominant tree height was marginally higher following CCPB than CLAAG and CC. Our results demonstrate that CCPB is beneficial to black spruce growth, presumably through its effects on forest understorey and SOL chemistry. While not similar to a high severity fire, prescribed burning after clearcut in paludified stands on the Clay Belt emulates some wildfire effects such as increasing soil pH. We suggest that unlike CLAAG, prescribed burning after clearcut can restore black spruce stand productivity and should be considered in the context of forest ecosystem management. [ABSTRACT FROM AUTHOR]

Several academic studies show that mutual funds set their prices in a strategic way according to their level of quality. This study examines a market in which two vertically differentiated mutual funds compete. Their price strategies are determined for the cases with complete and incomplete information. Our results show that mutual funds prefer to set their prices sequentially and that they are then indifferent to being the first or the second mover. With incomplete information, the presence of a lower quality mutual fund compels the high quality mutual fund to set lower prices at small levels of quality difference. [ABSTRACT FROM AUTHOR]

We study the strong ℋ 2 norm of systems modeled by semi-explicit Delay Differential Algebraic Equations (DDAEs). We recall that the finiteness of the strong ℋ 2 norm is linked to an algebraic decision problem that can be solved by checking a finite numbers of equalities. We first improve the verification of the finiteness condition. In particular, the complexity of our new condition removes a dependency on the number of delays. We also show that, without imposing further conditions on the system, the number of checks cannot be further reduced. The methodology relies on interpreting the verification of the finiteness conditions in terms of a Polynomial Identity Testing problem. Second we show, in a constructive way, that if the strong ℋ 2 norm is finite, the system can always be transformed into a regular neutral-type system with the same ℋ 2 norm, without derivatives in the input or in the output equations. This result closes a gap in the literature as such a transformation was known to exist only under additional assumptions on the system. The transformation enables the computation of the strong ℋ 2 norm using delay Lyapunov matrices. Illustrative examples are provided throughout the paper. [ABSTRACT FROM AUTHOR]

Résumé Depuis plus de trente ans, les chercheurs mènent des études afin de définir les formes d’intervention permettant d’améliorer les pratiques en matière de gestion des déchets. Notre étude se présente comme une revue de littérature des principales perspectives explorées en matière de techniques de communication et d’influence sur le tri et la prévention des déchets. En nous appuyant sur la classification des formes d’intervention sur la gestion des déchets proposée par Geller (1990), nous avons distingué quatre types d’interventions différentes : nous présentons successivement les travaux reposant sur les stratégies incitatives, rhétoriques et comportementales. Enfin, nous nous intéressons dans un dernier temps aux études ayant expérimenté une technique de feed-back. Nous soulevons pour chacune de ces approches les perspectives de recherche et d’application qui nous paraissent les plus pertinentes. For more than thirty years, researchers conduct studies to define the forms of intervention to improve the practices of waste management. This study is a review of literature interesting communication and influence on sorting and waste prevention. Building on the classification by Geller (1990) of types of intervention on the management of waste, we distinguished four different types of interventions: we present successively the work based on incentives, rhetorical and behavioral strategies. Finally, we present researchs which studied the feedback. We propose for each of these forms of influence techniques, prospects of research and application that seem most relevant. [ABSTRACT FROM AUTHOR]

Reaction of CeCl3 with an excess of LiTMP (TMP-H = 2,2,6,6-tetramethylpiperidine) gave [Ce(μ-OCH＝CH2)(TMP)2]2. The alkoxide ligand originated from THF, which was used as the solvent in the reaction. CeCl3 reacted with 3 equiv. of LiTMP in THF to produce, after crystallization, a 3:2 crystalline mixture of Ce(TMP)3 and [Ce(μ-OCH＝CH2)(TMP)2]2. Ce(TMP)3 could not be isolated cleanly or separated from the mixture except by handpicking the crystals under a microscope. The homoleptic amide complex Ce[N-t-Bu(SiMe3)]3 was obtained by reacting CeCl3(THF)2 with 3 equivalents of LiN-t-Bu(SiMe3). In the solid state, [Ce(μ-OCH＝CH2)(TMP)2]2 is a dimer with a Ce(μ-OR)2Ce four-member ring, while Ce(TMP)3 and Ce[N-t-Bu(SiMe3)]3 are trigonal planar monomers. There is structural evidence to suggest the presence of a Ce–vinyl group interaction in [Ce(μ-OCH＝CH2)(TMP)2]2. [Copyright &y& Elsevier]

Abstract: Interleukin-1β (IL-1β) is a crucial cytokine in inflammation processes and has been implicated in the pathogenesis of several chronic inflammatory diseases. Strategies designed to blocking IL-1β by passive administration of inhibitors (mAbs, IL-1 receptor antagonist) have previously demonstrated efficacy in rheumatoid arthritis (RA). Using molecular modelling, we have defined three murine IL-1β peptide regions characterized by their close proximity to the receptor. Synthetic peptides corresponding to these regions, in cyclic and linear form, were delivered as immunogens in Swiss mice, resulting in significant levels of autoantibodies directed against the native murine IL-1β cytokine as determined by ELISA and by an assay for neutralization of IL-1β biological activity. More importantly, one of the cyclic peptides showed a protective effect against inflammation and articular destruction in DBA/1 mouse collagen-induced arthritis, a model of RA. The high rate of success observed for active immunization against cytokine peptides in vivo suggests that the in silico approach to autoantigen design may be a promising avenue for the development of anti-cytokine immunotherapeutics. [Copyright &y& Elsevier]

The ketone body acetoacetate could be used as an alternate nutrient for the heart, and it also has the potential to improve cardiac function in an ischemic–reperfusion model or reduce the mitochondrial production of oxidative stress involved in cardiotoxicity. In this study, [ 11 C]-acetoacetate was investigated as an early marker of intracellular damage in heart failure. Methods A rat cardiotoxicity heart failure model was induced by doxorubicin, Dox(+). [ 14 C]-Acetoacetate, a non-positron (β −) emitting radiotracer, was used to characterize the arterial blood input function and myocardial mitochondrial uptake. Afterward, [ 11 C]-acetoacetate (β +) myocardial PET images were obtained for kinetic analysis and heart function assessment in control Dox(−) (n = 15) and treated Dox(+) (n = 6) rats. The uptake rate ( K 1 ) and myocardial clearance rate ( k 2 or k mono ) were extracted. Results [ 14 C]-Acetoacetate in the blood was increased in Dox(+), from 2 min post-injection until the last withdrawal point when the heart was harvested, as well as the uptake in the heart and myocardial mitochondria (unpaired t -test, p < 0.05). PET kinetic analysis of [ 11 C]-acetoacetate showed that rate constants K 1 , k 2 and k mono were decreased in Dox(+) ( p < 0.05) combined with a reduction of 24% of the left ventricular ejection fraction ( p < 0.001). Conclusion Radioactive acetoacetate ex vivo analysis [ 14 C], and in vivo kinetic [ 11 C] studies provided evidence that [ 11 C]-acetoacetate can assess heart failure Dox(+). Contrary to myocardial flow reserve (rest–stress protocol), [ 11 C]-acetoacetate can be used to assess reduced kinetic rate constants without requirement of hyperemic stress response. The proposed [ 11 C]-acetoacetate cardiac radiotracer in the investigation of heart disease is novel and paves the way to a potential role for [ 11 C]-acetoacetate in cardiac pathophysiology. [ABSTRACT FROM AUTHOR]