Biology subjects

Fitzgerald, N.

Publications and source records attributed to Fitzgerald, N..

3 recordsLinked to original sources

bioRxiv2025

Identification and Validation of Small Molecules with Mucin-Selective Regiospecific Binding in the Gastrointestinal Tract

Oral drug delivery is a widely used method of drug administration; however, achieving localized drug release at specific regions of the gastrointestinal (GI) tract is generally accomplished by using broad environmental differences. The GI tract is a complex system with regional differences in composition, such as selective expression of mucin glycoproteins in different organs. Here, we identify small molecule ligands that can selectively bind to the different mucins to localize drug delivery to the small intestine and stomach. We demonstrate up to a 10-fold increase in particle binding to these organs and up to a 4-fold increase in selectivity compared to chitosan. Additionally, we observe up to a 9-fold increase in budesonide concentration in the small intestine and a 25-fold increase in tetracycline concentration in the stomach. These results show that we have developed a versatile platform capable of sequestering a variety of drugs in certain GI tract organs.

bioengineering↗

bioRxiv2024

An Infralimbic Cortex Neuronal Ensemble Encoded During Learning Attenuates Fear Generalization Expression

Generalization allows previous experience to adaptively guide behavior when conditions change. The infralimbic (IL) subregion of the ventral medial prefrontal cortex plays a known role in generalization processes, although mechanisms remain unclear. A basic physical unit of memory storage and expression in the brain are sparse, distributed groups of neurons known as ensembles (i.e., the engram). Here, we set out to determine whether neuronal ensembles established in the IL during learning contribute to generalized responses. Generalization was tested in male and female mice by presenting a novel, ambiguous, tone generalization stimulus following Pavlovian defensive (fear) conditioning. The first experiment was designed to test a role for IL in generalization using chemogenetic manipulations. Results show IL regulates defensive behavior in response to ambiguous stimuli. IL silencing led to a switch in defensive state, from vigilant scanning to generalized freezing, while IL stimulation reduced freezing in favor of scanning. Leveraging activity-dependent "tagging" technology (ArcCreERT2 x eYFP system), a neuronal ensemble, preferentially located in IL Layer 2/3, was associated with the generalization stimulus. Remarkably, in the identical discrete location, fewer reactivated neurons were associated with the generalization stimulus at the remote timepoint (30 days) following learning. When an IL neuronal ensemble established during learning was selectively chemogenetically silenced, generalization increased. Conversely, IL neuronal ensemble stimulation reduced generalization. Overall, these data identify a crucial role for IL in suppressing generalized responses. Further, an IL neuronal ensemble, formed during learning, functions to later attenuate the expression of generalization in the presence of ambiguous threat stimuli.

neuroscience↗

bioRxiv2022

Drinkable, liquid in situ-forming and tough hydrogels for gastrointestinal therapeutics

Tablets and capsules are a cornerstone of medicine, but these solid dosage forms can be challenging to swallow for geriatric and pediatric patients. While liquid formulations are easier to ingest, these formulations lack the capacity to localize therapeutics and excipients nor act as controlled release devices. To bridge the advantages of solid and liquid dosage forms, here we describe drug formulations based on liquid in situ-forming and tough (LIFT) hydrogels. Drug-loaded LIFT hydrogels are formed directly in the stomach through the sequential ingestion of a crosslinker solution of calcium and dithiol crosslinkers, followed by the ingestion of a drug-containing polymer solution of alginate and 4-arm poly(ethylene glycol)-maleimide. We show that LIFT hydrogels are mechanically tough and able to robustly form in the presence of complex gastric fluid and in vivo in rat and porcine stomachs. LIFT hydrogels are retained within the porcine stomach for up to 24 h, biocompatible, and safely cleared. These hydrogels deliver a total dose comparable to unencapsulated drug but with delayed and lower maximum drug plasma concentrations, providing a method for controlled release that may mitigate drug toxicity. Co-encapsulation of lactase as a model biologic drug and calcium carbonate mitigated gastric-mediated deactivation of encapsulated enzyme in rat and porcine models. We also demonstrate the potential of these hydrogels to encapsulate and protect a model therapeutic bacterium, E. coli Nissle 1917, against acid. LIFT hydrogels present a biocompatible means of tough, double-network hydrogel formation in situ in the gastric cavity, and may expand medication access for patients with difficulty swallowing.

bioengineering↗