Arsenal of Nanobodies for Broad-Spectrum Countermeasures against Current and Future SARS-CoV-2 Variants of Concerns

Nanobodies offer several potential advantages over mAbs for the control of SARS-CoV-2. Their ability to access cryptic epitopes conserved across SARS-CoV-2 variants of concern (VoCs) and feasibility to engineer modular, multimeric designs, make these antibody fragments ideal candidates for developing broad-spectrum therapeutics against current and continually emerging SARS-CoV-2 VoCs. Here we describe a diverse collection of 37 anti-SARS-CoV-2 spike glycoprotein nanobodies extensively characterized as both monovalent and IgG Fc-fused bivalent modalities. The panel of nanobodies were shown to have high intrinsic affinity; high thermal, thermodynamic and aerosolization stability; broad subunit/domain specificity and cross-reactivity across many VoCs; wide-ranging epitopic and mechanistic diversity; high and broad in vitro neutralization potencies; and high neutralization efficacies in hamster models of SARS-CoV-2 infection, reducing viral burden by up to six orders of magnitude to below detectable levels. In vivo protection was demonstrated with anti-RBD and previously unreported anti-NTD and anti-S2 nanobodies. This collection of nanobodies provides a therapeutic toolbox from which various cocktails or multi-paratopic formats could be built to tackle current and future SARS-CoV-2 variants and SARS-related viruses. Furthermore, the high aerosol-ability of nanobodies provides the option for effective needle-free delivery through inhalation.

Making Good

This chapter assesses the “skill analogy” prominent in virtue ethics, which proposes that virtue be understood as a kind of expertise. Using the performance science literature, with special attention to skill development in chess, it is argued that the skill analogy is empirically undersupported, because a surprisingly limited amount is known about the development of skills in general, and “moral skills” in particular. It is further argued, given what is known about the domain specificity of expertise, that if virtues are to be understood along the lines of skills, they will have to be understood as highly domain specific, rather than as the highly general virtues of tradition.

Trusting the experts: The domain-specificity of prestige-biased social learning

Prestige-biased social learning (henceforth “prestige-bias”) occurs when individuals predominantly choose to learn from a prestigious member of their group, i.e. someone who has gained attention, respect and admiration for their success in some domain. Prestige-bias is proposed as an adaptive social-learning strategy as it provides a short-cut to identifying successful group members, without having to assess each person’s success individually. Previous work has documented prestige-bias and verified that it is used adaptively. However, the domain-specificity and generality of prestige-bias has not yet been explicitly addressed experimentally. By domain-specific prestige-bias we mean that individuals choose to learn from a prestigious model only within the domain of expertise in which the model acquired their prestige. By domain-general prestige-bias we mean that individuals choose to learn from prestigious models in general, regardless of the domain in which their prestige was earned. To distinguish between domain specific and domain general prestige we ran an online experiment (n = 397) in which participants could copy each other to score points on a general-knowledge quiz with varying topics (domains). Prestige in our task was an emergent property of participants’ copying behaviour. We found participants overwhelmingly preferred domain-specific (same topic) prestige cues to domain-general (across topic) prestige cues. However, when only domain-general or cross-domain (different topic) cues were available, participants overwhelmingly favoured domain-general cues. Finally, when given the choice between cross-domain prestige cues and randomly generated Player IDs, participants favoured cross-domain prestige cues. These results suggest participants were sensitive to the source of prestige, and that they preferred domain-specific cues even though these cues were based on fewer samples (being calculated from one topic) than the domain-general cues (being calculated from all topics). We suggest that the extent to which people employ a domain-specific or domain-general prestige-bias may depend on their experience and understanding of the relationships between domains.

Limited variation between SARS-CoV-2-infected individuals in domain specificity and relative potency of the antibody response against the spike glycoprotein

The spike protein of SARS-CoV-2 is arranged as a trimer on the virus surface, composed of three S1 and three S2 subunits. Infected and vaccinated individuals generate antibodies against spike, which can neutralize the virus. Most antibodies target the receptor-binding domain (RBD) and N-terminal domain (NTD) of S1; however, antibodies against other regions of spike have also been isolated. The variation between infected individuals in domain specificity of the antibodies and in their relative neutralization efficacy is still poorly characterized. To this end, we tested serum and plasma samples from 85 COVID-19 convalescent subjects using 7 immunoassays that employ different domains, subunits and oligomeric forms of spike to capture the antibodies. Samples were also tested for their neutralization of pseudovirus containing SARS-CoV-2 spike and of replication-competent SARS-CoV-2. We observed strong correlations between the levels of NTD- and RBD-specific antibodies, with a fixed ratio of each type to all anti-spike antibodies. The relative potency of the response (defined as the measured neutralization efficacy relative to the total level of spike-targeting antibodies) also exhibited limited variation between subjects, and was not associated with the overall amount of anti-spike antibodies produced. Accordingly, the ability of immunoassays that use RBD, NTD and different forms of S1 or S1/S2 as capture antigens to estimate the neutralizing efficacy of convalescent samples was largely similar. These studies suggest that host-to-host variation in the polyclonal response elicited against SARS-CoV-2 spike is primarily limited to the quantity of antibodies generated rather than their domain specificity or relative neutralization potency.

Mindset as Characteristic Adaptations: Using Response Surface Analysis to Assess Mindset in the Personality System

This study aimed to assess the congruencies and discrepancies between mindset domains in relation to well-being and sought to demonstrate that mindset falls into the characteristic adaptation level of personality. Data (N = 618, Mage = 16.07, SDage = 0.99) from Wave 1 of a longitudinal study on primarily ethnic-minority adolescents were used in response surface analyses to examine the effects of (in)congruence on well-being. The response surface analyses suggested no overall congruence effect between moral and ability mindsets. However, two-thirds of the participants demonstrated differing levels of mindsets, highlighting the domain specificity of mindsets. Results suggest that mindsets are contextual, domain-specific constructs, suiting the characteristic adaptation level of personality. Congruence for moral and ability mindset does not affect adolescent well-being.

A Semantic-Embedding Model-Driven Seq2Seq Method for Domain-Oriented Entity Linking on Resource-Restricted Devices

General entity linking systems usually leverage global coherence of all the mapped entities in the same document by using semantic embeddings and graph-based approaches. However, graph-based approaches are computationally expensive for open-domain datasets. In this paper, the authors overcome these problems by presenting an RDF embedding-based seq2seq entity linking method in specific domains. They filter candidate entities of mentions having similar meanings by using the domain information of the annotated pairs. They resolve high ambiguous pairs by using Bi-directional long short-term memory (Bi-LSTM) and attention mechanism for the entity disambiguation. To evaluate the system with baseline methods, they generate a dataset including book, music, and movie categories. They achieved 0.55 (Mi-F1), 0.586 (Ma-F1), 0.846 (Mi-F1), and 0.87 (Ma-F1) scores for high and low ambiguous datasets. They compare the method by using recent (WNED-CWEB) datasets with existing methods. Considering the domain-specificity of the proposed method, it tends to achieve competitive results while using the domain-oriented datasets.

An Objective Approach Toward Understanding Auditory Processing Disorder

Purpose In the field of audiology, auditory processing disorder (APD) continues to be a topic of ongoing debate for clinicians and scientists alike, both in terms of theory and clinical practice. In the current viewpoint, we first lay out the main issues that are central to the controversy surrounding APD, and then suggest a framework toward their resolution. Method The current viewpoint is informed by reviewing existing studies in the field of APD to better understand the issues contributing to the controversies in APD. Results We found that, within the current definition of APD, the two main issues that make the APD diagnosis controversial are (a) comorbidity with other disorders and (b) the lack of domain specificity. These issues remain unresolved, especially with the use of the existing behavioral APD test batteries. In this viewpoint, we shed light on how they can be mitigated by implementing the administration of an objective, physiological test battery. Conclusions By administering an objective test battery, as proposed in this viewpoint, we believe that it will be possible to achieve a higher degree of specificity to the auditory domain that will not only contribute towards clinical practice but also contribute towards strengthening APD as a theoretical construct.