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Abstract Coronavirus disease 2019 (COVID-19) continues to significantly impact the global population, thus countermeasure platforms that enable rapid development of therapeutics against variants of SARS-CoV-2 are essential. We report use of a phage display human antibody library approach to rapidly identify neutralizing antibodies (nAbs) against SARS-CoV-2. We demonstrate the binding and neutralization capability of two nAbs, STI-2020 and STI-5041, against the SARS-CoV-2 WA-1 strain as well as the Alpha and Beta variants. STI-2020 and STI-5041 were protective when administered intravenously or intranasally in the golden (Syrian) hamster model of COVID-19 challenged with the WA-1 strain or Beta variant. The ability to administer nAbs intravenously and intranasally may have important therapeutic implications and Phase 1 healthy subjects clinical trials are ongoing.

Abstract Insecticide application for vector control is the most controversial component of a public health program due to concerns about environmental and human health safety. One approach to overcome this challenge is the use of environmentally benign active ingredients. Among the most promising emerging strategies are attractive toxic sugar baits. Sugar alcohols—naturally occurring molecules safe for human consumption but potentially toxic to insects when ingested, have received increased attention for use with this approach. For this study, we screened the toxicity of four different sugar alcohols on several mosquito species, a biting midge, and a filth fly. Sugar alcohol mortalities exceeded those in the sucrose (positive control) only group. However, only erythritol and highly concentrated xylitol induced mortalities exceeding those in the water only (negative control) treatment ranging from approximately 40–75%. Formulations containing erythritol and xylitol should be further investigated under field conditions for efficacy in reducing populations of biting flies and for assessing potential non-target impacts.

Abstract Clostridioides difficile infection (CDI) remains a significant health threat worldwide. C. difficile is an opportunistic, toxigenic pathogen that takes advantage of a disrupted gut microbiome to grow and produce signs and symptoms ranging from diarrhea to pseudomembranous colitis. Antibiotics used to treat C. difficile infection are usually broad spectrum and can further disrupt the commensal gut microbiota, leaving patients susceptible to recurrent C. difficile infection. There is a growing need for therapeutic options that can continue to inhibit the outgrowth of C. difficile after antibiotic treatment is completed. Treatments that degrade C. difficile toxins while having minimal collateral impact on gut bacteria are also needed to prevent recurrence. Therapeutic bacteria capable of producing a range of antimicrobial compounds, proteases, and other bioactive metabolites represent a potentially powerful tool for preventing CDI recurrence following resolution of symptoms. Here, we describe the identification and initial characterization of ADS024 (formerly ART24), a novel therapeutic bacterium that can kill C. difficile in vitro with limited impact on other commensal bacteria. In addition to directly killing C. difficile, ADS024 also produces proteases capable of degrading C. difficile toxins, the drivers of symptoms associated with most cases of CDI. ADS024 is in clinical development for the prevention of CDI recurrence as a single-strain live biotherapeutic product, and this initial data set supports further studies aimed at evaluating ADS024 in future human clinical trials.

Abstract The ectoparasite Varroa destructor is the greatest threat to managed honey bee (Apis mellifera) colonies globally. Despite significant efforts, novel treatments to control the mite and its vectored pathogens have shown limited efficacy, as the host remains naïve. A prospective solution lies in the development of Varroa-resistant honey bee stocks, but a paucity of rigorous selection data restricts widespread adoption. Here, we characterise the parasite and viral dynamics of a Varroa-resistant honey bee stock, designated ‘Pol-line’, using a large-scale longitudinal study. Results demonstrate markedly reduced Varroa levels in this stock, diminished titres of three major viruses (DWV-A, DWV-B, and CBPV), and a two-fold increase in survival. Levels of a fourth virus that is not associated with Varroa—BQCV—do not differ between stocks, supporting a disruption of the transmission pathway. Further, we show that when decoupled from the influence of Varroa levels, viral titres do not constitute strong independent predictors of colony mortality risk. These findings highlight the need for a reassessment of Varroa etiology, and suggest that derived stocks represent a tractable solution to the Varroa pandemic.

Abstract Controlling and manipulating the propagation of surface plasmons has become a field of intense research given their potential in a wide range of applications, such as plasmonic circuits, optical trapping, sensors, and lensing. In this communication, we exploit classical optics techniques to design and evaluate the performance of plasmonic lenses with meniscus-like geometries. To do this, we use an adapted lens maker equation that incorporates the effective medium concepts of surface plasmons polaritons travelling in dielectric-metal and dielectric-dielectric-metal configurations. The design process for such plasmonic meniscus lenses is detailed and two different plasmonic focusing structures are evaluated: a plasmonic lens with a quasi-planar output surface and a plasmonic meniscus lens having a convex-concave input–output surface, respectively. The structures are designed to have an effective focal length of 2λ 0 at the visible wavelength of 633 nm. A performance comparison of the two plasmonic lenses is shown, demonstrating improvements to the power enhancement, with a 22% and 16.5% increase when using 2D (ideal) or 3D (realistic plasmonic) meniscus designs, respectively, compared to the power enhancement obtained with convex-planar lenses. It is also shown that the depth of focus of the focal spot presents a 19.8% decrease when using meniscus lenses in 2D and a 34.3% decrease when using the proposed 3D plasmonic meniscus designs. The broadband response of a plasmonic meniscus lens (550–750 nm wavelength range) is also studied along with the influence of potential fabrication errors on the generated effective focal length. The proposed plasmonic lenses could be exploited as alternative focusing devices for surface plasmons polaritons in applications such as sensing.

Abstract Megakaryocytes are a rare population of cells that develop in the bone marrow and function to produce platelets that circulate throughout the body and form clots to stop or prevent bleeding. A major challenge in studying megakaryocyte development, and the diseases that arise from their dysfunction, is the identification, classification, and enrichment of megakaryocyte progenitor cells that are produced during hematopoiesis. Here, we present a high throughput strategy for identifying and isolating megakaryocytes and their progenitor cells from a heterogeneous population of bone marrow samples. Specifically, we couple thrombopoietin (TPO) induction, image flow cytometry, and principal component analysis (PCA) to identify and enrich for megakaryocyte progenitor cells that are capable of self-renewal and directly differentiating into mature megakaryocytes. This enrichment strategy distinguishes megakaryocyte progenitors from other lineage-committed cells in a high throughput manner. Furthermore, by using image flow cytometry with PCA, we have identified a combination of markers and characteristics that can be used to isolate megakaryocyte progenitor cells using standard flow cytometry methods. Altogether, these techniques enable the high throughput enrichment and isolation of cells in the megakaryocyte lineage and have the potential to enable rapid disease identification and diagnoses ahead of severe disease progression.

Tissue engineering approaches have the potential to increase the physiologic relevance of human iPS-derived cells, such as cardiomyocytes (iPS-CM). However, forming Engineered Heart Muscle (EHM) typically requires >1 million cells per tissue. Existing miniaturization strategies involve complex approaches not amenable to mass production, limiting the ability to use EHM for iPS-based disease modeling and drug screening. Micro-scale cardiospheres are easily produced, but do not facilitate assembly of elongated muscle or direct force measurements. Here we describe an approach that combines features of EHM and cardiospheres: Micro-Heart Muscle (μHM) arrays, in which elongated muscle fibers are formed in an easily fabricated template, with as few as 2,000 iPS-CM per individual tissue. Within μHM, iPS-CM exhibit uniaxial contractility and alignment, robust sarcomere assembly, and reduced variability and hypersensitivity in drug responsiveness, compared to monolayers with the same cellular composition. μHM mounted onto standard force measurement apparatus exhibited a robust Frank-Starling response to external stretch, and a dose-dependent inotropic response to the β-adrenergic agonist isoproterenol. Based on the ease of fabrication, the potential for mass production and the small number of cells required to form μHM, this system provides a potentially powerful tool to study cardiomyocyte maturation, disease and cardiotoxicology in vitro.

Drug discovery and development are hampered by high failure rates attributed to the reliance on non-human animal models employed during safety and efficacy testing. A fundamental problem in this inefficient process is that non-human animal models cannot adequately represent human biology. Thus, there is an urgent need for high-content in vitro systems that can better predict drug-induced toxicity. Systems that predict cardiotoxicity are of uppermost significance, as approximately one third of safety-based pharmaceutical withdrawals are due to cardiotoxicty. Here, we present a cardiac microphysiological system (MPS) with the attributes required for an ideal in vitro system to predict cardiotoxicity: i) cells with a human genetic background; ii) physiologically relevant tissue structure (e.g. aligned cells); iii) computationally predictable perfusion mimicking human vasculature; and, iv) multiple modes of analysis (e.g. biological, electrophysiological, and physiological). Our MPS is able to keep human induced pluripotent stem cell derived cardiac tissue viable and functional over multiple weeks. Pharmacological studies using the cardiac MPS show half maximal inhibitory/effective concentration values (IC₅₀/EC₅₀) that are more consistent with the data on tissue scale references compared to cellular scale studies. We anticipate the widespread adoption of MPSs for drug screening and disease modeling.