Biology subjects

Gregory, L.

Publications and source records attributed to Gregory, L..

4 recordsLinked to original sources

bioRxiv2026

Evolutionary adaptation of helminth immunomodulators to their hosts

Background: Parasitic nematodes have evolved secreted effector proteins which interact with host molecules to modulate the host immune response. These interactions can be highly specific and are under strong selective pressure. Here, we investigate the host-pathogen interaction between Heligmosomoides bakeri and its natural host Mus musculus, and between H. polygyrus and its natural host Apodemus sylvaticus. We focus on the Alarmin Release Inhibitor family (previously called HpARI) produced by heligmosomid parasites, which interact with IL-33 and heparan sulphate. Results: Using comparative genomics, we identified duplications and diversifications of the ARI family including multiple copies of ARI1 and conserved ARI3 homologues in both H. bakeri and H. polygyrus. We identify a new family member, HpolARI4, encoded by H. polygyrus, as well as a more distant homologue, HmixARI, encoded by Heligmosomum mixtum, a parasite of the bank vole (Myodes glareolus). Our functional assays identify that HpolARI4 preferentially blocks A. sylvaticus IL-33 but has little activity against M. musculus IL-33, whereas HbakARI2 is highly specific for M. musculus IL-33. We furthermore show differential interaction with host heparan sulphate, with HbakARI2 and HpolARI4 showing high affinity binding, whereas HbakARI3 shows no binding. We further test this family against non-host human IL-33 and show that functional suppression can be achieved by HbakARI3 in vitro and in vivo. Conclusion: By integrating genomic data, structural insights, and functional assays, we reveal how the expansion and diversification of the ARI family drive host-specific IL-33 modulation, providing a molecular model for nematode-host co-evolution.

immunology↗

bioRxiv2026

Embryonic environment impacts adult traits and phenotypic integration in the pea aphid

Understanding how the embryonic environment affects adult phenotype is critical in the context of both human health and the increasing variance of environmental conditions due to climate change. Here we consider this topic within the framework of phenotypic integration, i.e., the pattern of correlations among elements of functionally robust trait suites. We investigated the life-long consequences of alternative embryonic environments on phenotypic integration in the pea aphid (Acyrthosiphon pisum). We exposed live-bearing pea aphid mothers to an adverse, high-density environment or a benign, low-density environment and measured morphological traits, fecundity, and transcriptional profiles in the resulting winged and wingless adult offspring. We observe that morphological integration decreases in both morphs in response to the adverse maternal environment. Transcriptional integration, on the other hand, shows a morph-specific response: integration increases in wingless offspring but decreases in winged offspring in response to the adverse maternal environment. Our results show the remarkable phenotypic diversity that a single genotype can express in response to environmental variation; that maternal environmental conditions can have strong effects on offspring trait variation and trait integration; and that these effects differ at the morphological and transcriptional levels.

evolutionary biology↗

bioRxiv2025

Predicting Human Pharmacokinetic Parameters of Drugs using a Multi-Tissue Chip Platform Integrating Liver, Kidney, and Skeletal Muscle Microphysiological Systems

Accurate prediction of human pharmacokinetic (PK) parameters remains a critical challenge in drug discovery. While simple in vitro assays provide insight into discrete metabolic processes, they cannot recapitulate the complex multi-organ interactions that involve absorption, distribution, metabolism, and excretion (ADME) processes. This limitation has perpetuated a heavy reliance on animal experimentation to predict integrated outcomes like hepatic and renal clearance in humans. In this study, we developed a multi-tissue chip (MTC) to evaluate the PK parameters of intravenously (IV) administered drugs. The MTC platform provides continuous oxygenation through media recirculation and interconnects three MPSs (liver, kidney, skeletal muscle) to study drug metabolism, excretion and distribution within a single in vitro system. The functionality of each MPS was characterized for more than 15 days with single- and multi-tissue chips. A diverse set of drugs from all extended clearance classification system (ECCS) classes with various clearance mechanisms was evaluated on the MTCs and on-chip PK parameters were evaluated, such as hepatic metabolism, uptake, and disposition, tubular secretion and reabsorption, and muscle distribution. These PK parameters were successfully correlated to clinical parameters for IV drugs: hepatic clearance (CLH), renal clearance (CLR), volume of distribution (VD) and then these parameters were extrapolated to human drug exposures using physiologically-based pharmacokinetic (PBPK) modeling. This study demonstrated that the MTC platform could deliver accurate prediction for clinical pharmacokinetics of intravenously administered small molecules without the need for animal studies.

bioengineering↗

bioRxiv2023

A Novel Milli-fluidic Liver Tissue Chip with continuous Recirculation for Predictive pharmacokinetics Applications

A crucial step in lead selection during drug development is accurate estimation and optimization of hepatic clearance using in vitro methods. However, current methods are limited by factors such as lack of physiological relevance, short culture/incubation times that are not consistent with drug exposure patterns in patients, use of drug absorbing materials, and evaporation during long-term incubation. To address these technological needs, we developed a novel milli-fluidic human liver tissue chip (LTC) that was designed with continuous media recirculation and optimized for hepatic cultures using human primary hepatocytes. Here, we characterized the LTC using a series of physiologically relevant metrics and test compounds to demonstrate that we could accurately predict the PK of both low and high clearance compounds. The non-biological characterization indicated that the cyclic olefin copolymer (COC)-based LTC exhibited negligible evaporation and minimal non-specific binding of drugs of varying ionic states and lipophilicity. Biologically, the LTC exhibited functional and polarized hepatic culture with sustained metabolic CYP activity for at least 15 days. This long-term culture was then used for drug clearance studies for low and high-clearance compounds for at least 12 days and clearance was estimated for a range of compounds with high in vitro in vivo correlation (IVIVC). We also demonstrated that LTC can be induced by rifampicin, and the culture age had insignificant effect on depletion kinetic and predicted clearance value. Thus, we used advances in bioengineering to develop a novel purpose-built platform with high reproducibility and minimal variability to address unmet needs for PK applications.

pharmacology and toxicology↗