Emergent BioSolutions (Canada)

Background/Objectives: The rapid development of safe and efficacious vaccines is often hindered by extensive, mandated non-clinical safety evaluations in animals. With the aim to provide scientific evidence supporting a "vaccine platform approach", here we present the complete non-clinical studies for two investigational vaccines, GRAd-COV2 and GRAdHIVNE1, based on GRAd, a gorilla-derived group C adenoviral vector. Methods: The biodistribution of GRAd genomes following the intramuscular administration of the vaccines was assessed in rats by a sensitive qPCR method. Local tolerance and systemic toxic effects were evaluated in single- and repeated-dose toxicity studies in rabbits. Results: GRAd-COV2 and GRAdHIVNE1 were well-tolerated. Distribution was highly confined to the injection site and draining lymph nodes, and toxicity profile consisted of transient, non-adverse inflammatory responses, while the expected immune responses to the encoded antigens were successfully induced. Notably, both vaccines demonstrated a consistent safety profile despite transgene and backbone differences, comparable to other replication-defective adenoviral vectors. Conclusions: The established non-clinical safety profile of the GRAd platform provides a robust foundation for a more efficient and streamlined regulatory pathway. By leveraging this prior knowledge, future GRAd-based vaccines can achieve accelerated clinical development while fully adhering to the ethical principles of replacement, reduction, and refinement of animal use in research.

Background/Objectives: We have established a robust, cell-based high-throughput screening platform capable of identifying SARS-CoV-2 entry inhibitors within a BSL-2 facility. Methods: Using a curated compound library, we conducted a screening campaign that led to the discovery of potent viral entry inhibitors active in both pseudoviral and infectious SARS-CoV-2 inhibition assays. Results: Among those, Hit-1 exhibited submicromolar antiviral activity across all tested SARS-CoV-2 strains, including the highly transmissible Omicron subvariants. Biophysical binding assays confirmed that Hit-1 and related compounds directly engage the prefusion-stabilized SARS-CoV-2 spike proteins of both authentic WA1/2020 and Omicron viral strains. To elucidate potential binding orientations and interactions of the hit compounds with the SARS-CoV-2 spike protein, molecular docking studies were performed targeting two putative binding sites. Conclusions: Preliminary structure–activity relationship studies identified a promising subset of drug-like 7,8-dihydropyrido[4,3-d]pyrimidine-based inhibitors with potential for further development as novel therapeutic agents aimed at blocking viral entry and thereby preventing or mitigating SARS-CoV-2 infection. Among these, compound 13 stands out due to its superior in vitro potency and favorable pharmacokinetic properties, positioning it as a strong candidate for in vivo efficacy evaluation.

ABSTRACT Faced with the emergence of three epidemics linked to a virus from the coronaviridæ family over the last 20 years (SARS-CoV in China in 2002, MERS-CoV in Arabia in 2012, and SARS- CoV-2 worldwide in 2019), the identification of new antiviral treatments is of major public health concern. As part of the development of new drugs, several molecular modeling tools such as docking, virtual screening and molecular dynamics were combined with databases to decipher potential inhibitors of coronavirus targets. We performed a structure-based design of antiviral drugs targeting SARS-CoV-2 non-structural proteins 3 and 5 (nsp3 and nsp5) based on a high-throughput virtual screening of the ZINC15 database tranches for ligand docking followed by click chemistry with a particular attention paid to relaxed structures mimicking potential in vivo interactions. Based on the above in silico approaches, we selected two small molecules with high affinity binding for nsp3 and nsp5 named Amb929 and Amb701, respectively. We then assessed the antiviral activity of both the Amb929 and Amb701 against SARS-CoV-2 infection taking into account their potential cytotoxicity. Although both compounds inhibited SARS-CoV-2 replication in vitro , Amb929 displayed the most efficient anti-SARS-CoV-2 activity. Among these two drugs, Amb929 was less cytotoxic compared to Amb701, demonstrating an optimal anti-SARS-CoV-2 response with a high selectivity index in cell culture and a high inhibition of SARS-CoV-2 replication compared to untreated condition on a model of human airway epithelium (HAE), paving the way for the development of drugs with very potent anti-coronavirus activity.

Integrating renewable energy into microgrids facilitates peer-to-peer (P2P) energy trading between prosumers and consumers. However, variability in renewable power generation and dynamic consumer demand pose challenges to grid stability and trading mechanisms. This paper presents a forecasting method for available power from renewable-integrated households, focusing on Very short-term surplus power prediction for trading within a microgrid. The approach uses Internet of Things (IoT) monitoring, Long Short-Term Memory (LSTM) forecasting models, and the OpenDSS platform. The system includes an IoT-Photovoltaic (PV)-Grid Monitoring Unit to track power and indoor temperature, and an IoT-based Irradiance and Temperature Monitoring Unit for outdoor conditions. The monitored data is input into the LSTM model, and forecasted data is used in the OpenDSS DemandSide Management System (O-DSM) to predict PV generation and load behaviour in the microgrid at one-minute intervals over 15 minutes. The simulation provides insights into microgrid operations, energy flow, voltage profiles, and surplus power availability for trading, while the forecasting data supports trading decisions with peers. This research demonstrates the use of lightweight IoT devices and a cost-effective Raspberry Pi 5-based forecasting unit to enhance sustainable energy trading through improved forecasting and real-time data integration.

In this report, we present a facile, efficient, and green strategy for the preparation of fluorescent carbon quantum dots (CQDs) for bioimaging applications.

The energy transition calls for natural hydrogen exploration, with most occurrences discovered either inadvertently or, more recently, at the location of potentially diffusive circles observed from a change of vegetation cover at the surface. However, some notable hydrogen occurrences are not directly associated with the presence of diffusive circles like the Bourakebougou field in Mali. Thus, the objective of this work was to highlight geological areas that have some potential to find natural hydrogen in Quebec, a Canadian province where no diffusive circles have yet been documented but which is rich in potential source rocks and where no exploration for natural hydrogen has been undertaken so far. A review of the different geological regions of Quebec was undertaken to highlight the relevant characteristics and geographical distribution of geological assemblages that may produce or have produced natural hydrogen, in particular, iron-rich rocks but also uranium-rich rocks, supramature shales and zones where significant structural discontinuities are documented or suspected, which may act as conduits for the migration of fluids of mantle origin. In addition to regional and local geological data, an inventory of available geochemical data is also carried out to identify potential tracers or proxies to facilitate subsequent exploration efforts. A rating was then proposed based on the quality of the potential source rocks, which also considers the presence of reservoir rocks and the proximity to end-users. This analysis allowed rating areas of interest for which fieldwork can be considered, thus minimizing the exploratory risks and investments required to develop this resource. The size of the study area (over 1.5 million km2), the diversity of its geological environments (from metamorphic cratons to sedimentary basins) and their wide age range (from Archean to Paleozoic) make Quebec a promising territory for natural hydrogen exploration and to test the systematic rating method proposed here.

The Riemann zeta function $\zeta(s):= \sum_{n=1}^{\infty} 1/n^s$ can be interpreted as the energy per point of the lattice $\mathbb{Z}$, interacting pairwisely via the Riesz potential $1/r^s$. Given a parameter $\Delta\in (0,1]$, this physical model is generalized by considering the energy per point $E(s,\Delta)$ of a periodic one-dimensional lattice alternating the distances between the nearest-neighbour particles as $2/(1+\Delta)$ and $2\Delta/(1+\Delta)$, keeping the lattice density equal to one independently of $\Delta$. This energy trivially satisfies $E(s,1)=\zeta(s)$ at $\Delta=1$, it can be easily expressed as a combination of the Riemann and Hurwitz zeta functions, and extended analytically to the punctured $s$-plane $\mathbb{C} \setminus \{ 1\}$. In this paper, we perform numerical investigations of the zeros of the energy $\{ \rho=\rho_x+{\rm i}\rho_y\}$, which are defined by $E(\rho,\Delta)=0$. The numerical results reveal that in the Riemann limit $\Delta\to 1^-$ theses zeros include the anticipated critical zeros of the Riemann zeta function with $\Re(\rho_x)=\frac{1}{2}$ as well as an unexpected -- comparing to the Riemann Hypothesis -- infinite series of off-critical zeros. The analytic treatment of these off-critical zeros shows that their imaginary components are equidistant and their real components diverge logarithmically to $-\infty$ as $\Delta\to 1^-$, i.e., they become invisible at the Riemann's $\Delta=1$.

Aixiang Li created the cover image that shows a heparin unit-containing graft copolymer CA-g-P(AA/SSS), which was prepared by grafting acrylic acid (AA) and sodium styrene sulfonate (SSS) onto cellulose acetate (CA) to coat the adsorbent resin for disposable hemoperfusion devices. The modified CA-coated adsorbent resin had a good adsorption effect on small and medium-sized molecules such as creatinine, vitamin B12, bilirubin, and imidacloprid. And the coating could greatly improve the blood compatibility and biocompatibility of the adsorbent resin, which can be used in uremia, hyperbilirubinemia, and rapid treatment of pesticide poisoning. DOI: 10.1002/app.53895 [Correction added on April 20, 2023, after first online publication: Author's spelling in the cover caption has been corrected as Aixiang Li.]