Biology subjects

Barker, S. J.

Publications and source records attributed to Barker, S. J..

4 recordsLinked to original sources

bioRxiv2025

Operando Monitoring of Metabolic Fluxes In Cholestatic Murine Liver Tissue Slices By Microfluidic Nuclear Magnetic Resonance

Monitoring metabolism in living tissues with high temporal resolution and broad metabo-lite coverage remains a major challenge. We introduce TISuMR, a microfluidic Lab-on-a-Chip platform that enables continuous, non-invasive operando NMR spectroscopy of live tissue slices. The TISuMR platform replaces the conventional NMR sample tube with a fully integrated microfluidic culture system that maintains tissue viability through dynamic nutrient perifusion, gas exchange via a diffusion membrane, and precise temperature control. Coupled with a custom-designed micro-NMR probe, the platform allows detection of nearly two dozens of metabolites from just 2.5 {micro}L of sample. In a proof-of-concept study, we demonstrate the platforms unique ability to resolve dynamic metabolic fluxes and to monitor, in real time, the onset of chlorpromazine-induced cholestasis in murine liver tissue, with a time resolution of just over three minutes. This approach provides a powerful, minimally disruptive tool for studying tissue metabolism in real time.

bioengineering↗

bioRxiv2024

Species richness patterns in Fijian bees are explained by constraints in physiological traits

Determining the ecological and evolutionary mechanisms that underpin patterns of species richness across elevational gradients is a key question in evolutionary ecology, and can help to understand species extinction risk under changing climates. In the tropical montane islands of Fiji, there are 28 species of endemic bee in the subgenus Lasioglossum (Homalictus), where species richness increases with elevation despite decreasing land surface (habitat) areas. We used a combination of spatially explicit phylogenetic diversity analyses and phylogenetic trait analyses to examine the factors shaping species distributions in these bees. We found that species at higher elevations had lower heat tolerance and desiccation resistance than those at lower elevations, consistent with these traits constraining species elevational ranges. We also found high species phylogenetic diversity within mountains, and high phylogenetic signal in species heat tolerance and minimum elevational ranges, consistent with these traits being evolutionarily conserved among mountain-top taxa following vicariant (allopatric) speciation. We found no evidence to suggest that interspecific competition is shaping species elevational ranges. In all, our findings indicate that phylogenetic conservatism in physiological traits related to climatic niche, such as heat tolerance, can explain why species richness is highest at mountain tops in this system, with species having tracked their climatic niches over time towards ever higher (cooler and wetter) elevations. Because high elevations in this archipelago are extremely limited ([~]2.3% of total land area), only miniscule elevational islands in the sky remain into which this diverse, but climate-restricted fauna, can retreat as climates warm.

evolutionary biology↗

bioRxiv2023

Targeting Transferrin Receptor to Transport Antisense Oligonucleotides Across the Blood-Brain Barrier

Antisense oligonucleotides (ASO) are promising therapies for neurological disorders, though they are unable to cross the blood-brain barrier (BBB) and must be delivered directly to the central nervous system (CNS). Here, we use a human transferrin receptor (TfR)-binding molecule to transport ASO across the BBB in mice and non-human primates, termed oligonucleotide transport vehicle (OTV). Systemically delivered OTV drives significant, cumulative, and sustained knockdown of the ASO target across multiple CNS regions and all major cell types. Further, systemic OTV delivery enables more uniform ASO biodistribution and knockdown compared to two other clinically relevant ASO delivery routes: a standard, high affinity TfR antibody, or direct ASO delivery to the CSF. Together, our data support systemically delivered OTV as a potential therapeutic platform for neurological disorders. One-Sentence SummarySystemically dosed OTV delivered via TfR1 targeting shows widespread and cumulative target knockdown in the mouse and NHP CNS.

neuroscience↗

bioRxiv2020

A cyclin-dependent kinase 5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes

Aberrant activity of cyclin-dependent kinase (Cdk5) has been implicated in various neurodegenerative diseases. This effect is mediated by pathological cleavage of the Cdk5 activator p35 to produce the truncated product p25, exhibiting increased stability and altered substrate specificity. The benefit of blocking p25 production has been demonstrated in various rodent and human neurodegenerative models. However, important Cdk5/p35 functions in the developing and adult brain have made it challenging to selectively target the detrimental effects of Cdk5/p25 while sparing the physiological functions of Cdk5/p35. Here, we report a 12-amino acid-long peptide fragment derived from Cdk5 (the Cdk5 inhibitory (Cdk5i) peptide) that shows a high binding affinity toward the Cdk5/p25 complex and can efficiently and selectively inhibit Cdk5/p25 kinase activity. Using cellular assays, mouse neurodegeneration models and human cerebral organoids generated from patient-derived iPSCs, we demonstrate beneficial effects of the Cdk5i peptide on various pathological phenotypes including gliosis, DNA damage, and Tau hyperphosphorylation.

neuroscience↗