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Williams, A. B.

Publications and source records attributed to Williams, A. B..

2 recordsLinked to original sources

Proximity to Boundaries Reveals Spatial Context Representation in Human Hippocampal CA1

Recollection of real-world events is often accompanied by a sense of being in the place where the event transpired. Convergent evidence suggests the hippocampus plays a key role in supporting episodic memory by associating information with the time and place it was originally encountered. This representation is reinstated during memory retrieval. However, little is known about the roles of different subfields of the human hippocampus in this process. Research in humans and non-human animal models have suggested that spatial environmental boundaries have a powerful influence on spatial and episodic memory, as well as hippocampal representations of contexts and events. Here, we used high-resolution fMRI to investigate how boundaries influence hippocampal activity patterns during the recollection of objects encountered in different spatial contexts. During the encoding phase, participants viewed objects once in a naturalistic virtual reality task, in which they passively explored two rooms in one of two houses. Following the encoding phase, participants were scanned while they recollected items in the absence of any spatial contextual information. Our behavioral results demonstrated that spatial context memory was enhanced for objects encountered near a boundary. Activity patterns in CA1 carried information about the spatial context associated with each of these boundary items. Exploratory analyses revealed that memory for the room in which each object was studied was correlated with the fidelity of retrieved spatial context representations in anterior parahippocampal cortex and subiculum. Our results highlight the privileged role of boundaries in CA1 and suggest more generally a close relationship between memory for spatial contexts and representations in the hippocampus and parahippocampal region.

neuroscience↗

An optimized live bacterial delivery platform for the production and delivery of therapeutic nucleic acids and proteins

There is an unmet need for delivery platforms that realize the full potential of next-generation therapeutic and vaccine technologies, especially those that require intracellular delivery of nucleic acids. The in vivo usefulness of the current state-of-the-art delivery systems is limited by numerous intrinsic weaknesses, including lack of targeting specificity, inefficient entry and endosomal escape into target cells, undesirable immune activation, off-target effects, a small therapeutic window, limited genetic encoding and cargo capacity, and manufacturing challenges. Here we present our characterization of a delivery platform based on the use of engineered live, tissue-targeting, non-pathogenic bacteria (Escherichia coli strain SVC1) for intracellular cargo delivery. The SVC1 bacteria are engineered to specifically bind to epithelial cells via a surface-expressed targeting ligand, to escape the endosome upon intracellularization, and to have minimal immunogenicity. Here we report findings on key features of this system. First, we demonstrated that bacterial delivery of a short hairpin RNA (shRNA) can target and silence a gene in an in vitro mammalian respiratory cell model. Next, we used an in vivo mouse model to demonstrate that SVC1 bacteria are invasive to epithelial cells of various tissues and organs (eye, nose, mouth, stomach, vagina, skeletal muscle, and lungs) via local administration. We also showed that repeat dosing of SVC1 bacteria to the lungs is minimally immunogenic and that it does not have adverse effects on tissue homeostasis. Finally, to validate the potential of SVC1 bacteria in therapeutic applications, we demonstrated that bacterial delivery of influenza-targeting shRNAs to the respiratory tissues can mitigate viral replication in a mouse model of influenza infection. Our ongoing work is focused on further refining this platform for efficient delivery of nucleic acids, gene editing machinery, and therapeutic proteins, and we expect that this platform technology will enable a wide range of advanced therapeutic approaches.

microbiology↗