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Biology subjects

Xu, A. Z.

Publications and source records attributed to Xu, A. Z..

3 recordsLinked to original sources

Flexible selection of working memory representations to reduce cognitive cost

Across psychology 1-4, economics 5,6, machine learning 7, and neuroscience 8,9, it is well established that choosing a good internal representation can make complex problems easier to solve. Thus, intelligent behavior depends not only on what is stored in working memory, but on the format in which it is stored. Selecting a lower-load format can substantially reduce the mental effort required for a task, since working-memory load is a major contributor to cognitive cost 10-12. Whether non-human animals make such representational choices, and how these choices are implemented in neural circuits, has remained unclear. Here we show that rats flexibly adjust the format of working memory to reduce cognitive cost. In an egocentric task that encourages an action-based code, rats maintained the relevant information as a stable motor plan supported by frontal cortex. When the same behavioral problem was reformulated in allocentric coordinates, the action-based code became costly, and rats instead stored a sensory trace in auditory cortex. A cost-sensitive model explains which internal format should be used under each task variant and predicted that simplifying the allocentric task would reduce the advantage of a sensory code and drive reinstatement of frontal motor planning; this prediction was confirmed, as rats rapidly returned to a motorplan representation and the frontal cortex again became necessary for performance. These results demonstrate that flexible representational selection is not unique to humans 13 but is present in rodents and reflected in circuit-level reallocation of working memory. This establishes a neural basis for classic theories linking problem representation to computational efficiency and provides a path toward a circuit-level understanding of how the brain selects internal formats to reduce cognitive cost.

neuroscience↗

An adjuvanted SARS-CoV-2 RBD nanoparticle elicits neutralizing antibodies and fully protective immunity in aged mice

Development of affordable and effective vaccines that can also protect vulnerable populations such as the elderly from COVID-19-related morbidity and mortality is a public health priority. Here we took a systematic and iterative approach by testing several SARS-CoV-2 protein antigens and adjuvants to identify a combination that elicits neutralizing antibodies and protection in young and aged mice. In particular, SARS-CoV-2 receptorbinding domain (RBD) displayed as a protein nanoparticle (RBD-NP) was a highly effective antigen, and when formulated with an oil-in-water emulsion containing Carbohydrate fatty acid MonoSulphate derivative (CMS) induced the highest levels of cross-neutralizing antibodies compared to other oil-in-water emulsions or AS01B. Mechanistically, CMS induced antigen retention in the draining lymph node (dLN) and expression of cytokines, chemokines and type I interferon-stimulated genes at both injection site and dLN. Overall, CMS:RBD-NP is effective across multiple age groups and is an exemplar of a SARS-CoV-2 subunit vaccine tailored to the elderly.

immunology↗

Alum:CpG adjuvant enables SARS-CoV-2 RBD-induced protection in aged mice and synergistic activation of human elder type 1 immunity

Global deployment of vaccines that can provide protection across several age groups is still urgently needed to end the COVID-19 pandemic especially for low- and middle-income countries. While vaccines against SARS-CoV-2 based on mRNA and adenoviral-vector technologies have been rapidly developed, additional practical and scalable SARS-CoV-2 vaccines are needed to meet global demand. In this context, protein subunit vaccines formulated with appropriate adjuvants represent a promising approach to address this urgent need. Receptor-binding domain (RBD) is a key target of neutralizing antibodies (Abs) but is poorly immunogenic. We therefore compared pattern recognition receptor (PRR) agonists, including those activating STING, TLR3, TLR4 and TLR9, alone or formulated with aluminum hydroxide (AH), and benchmarked them to AS01B and AS03-like emulsion-based adjuvants for their potential to enhance RBD immunogenicity in young and aged mice. We found that the AH and CpG adjuvant formulation (AH:CpG) demonstrated the highest enhancement of anti-RBD neutralizing Ab titers in both age groups ([~]80-fold over AH), and protected aged mice from the SARS-CoV-2 challenge. Notably, AH:CpG-adjuvanted RBD vaccine elicited neutralizing Abs against both wild-type SARS-CoV-2 and B.1.351 variant at serum concentrations comparable to those induced by the authorized mRNA BNT162b2 vaccine. AH:CpG induced similar cytokine and chemokine gene enrichment patterns in the draining lymph nodes of both young adult and aged mice and synergistically enhanced cytokine and chemokine production in human young adult and elderly mononuclear cells. These data support further development of AH:CpG-adjuvanted RBD as an affordable vaccine that may be effective across multiple age groups. One Sentence SummaryAlum and CpG enhance SARS-CoV-2 RBD protective immunity, variant neutralization in aged mice and Th1-polarizing cytokine production by human elder leukocytes.

immunology↗