Biology subjects

Hills, K.

Publications and source records attributed to Hills, K..

2 recordsLinked to original sources

bioRxiv2026

Dual targeting a LIN28B:β-catenin axis in acute myeloid leukaemia

BackgroundWnt/{beta}-catenin signalling is dysregulated in acute myeloid leukaemia (AML), where it lacks effective targeting strategies. Previously, we discovered that {beta}-catenin interacts with several RNA-binding proteins (RBP), indicating post-transcriptional influence which is yet to be therapeutically interrogated in AML. MethodsCo-immunoprecipitation confirmed protein interactions, and TCF/LEF reporters were used to assess Wnt signalling output in leukaemia cells. Regulatory crosstalk was assessed using immunoblotting and RT-qPCR approaches following lentiviral transduction of myeloid cell lines. Targeting of {beta}-catenin and LIN28B was tested through combinations of genetic and pharmacological inhibition in AML cells. ResultsThe most frequent RBP-binding motif amongst {beta}-catenin-bound mRNAs was the GGAG motif targeted by oncofetal miRNA-regulating RBP; LIN28B. {beta}-Catenin:LIN28B interactions were detected in lymphoid and myeloid cell lines, plus primary human CD34 fetal-liver HSCs. LIN28B positively regulated Wnt signalling output through LEF1 regulation involving a post-transcriptional let7 miRNA mechanism. Further miRNA sequencing of {beta}-catenin- and LIN28B-depleted myeloid cells revealed potential cooperative and antagonistic function in miRNA regulation. Finally, dual-targeting both {beta}-catenin and LIN28B through either genetic and/or pharmacological means preferentially reduced AML cell viability. ConclusionThe {beta}-catenin:LIN28B axis could represent a novel synthetically lethal relationship in AML which could be exploited in rare subtypes where LIN28B expression becomes reactivated.

cancer biology↗

bioRxiv2024

Flexible graphene-based neurotechnology for high-precision deep brain mapping and neuromodulation in Parkinsonian rats

Deep brain stimulation (DBS) is a neuroelectronic therapy for the treatment of a broad range of neurological disorders, including Parkinsons disease. Current DBS technologies face important limitations that impact their efficacy, such as large electrode size, invasiveness, and lack of adaptive therapy based on biomarker monitoring. The use of novel electrode materials is expected to contribute to overcome these limitations. In a previous study, we reported that nanoporous reduced graphene oxide (rGO) is a promising electrode material due to its high charge injection capacity and low impedance. Here, we investigate the potential benefits of using the rGO technology in DBS. To this end, we implant a flexible high-density array of rGO microelectrodes in the subthalamic nucleus (STN) of healthy and hemi-parkinsonian rats to investigate specific electrophysiological Parkinsonian biomarkers and to assess the effect of microscale stimulation. We demonstrate that these microelectrodes record action potentials with high signal-to-noise ratios (SNR > 6), allowing the precise localization of deep brain structures like the STN, and the tracking of multiunit-based biomarkers such as STN bursts. The bidirectional capability to deliver high-density focal stimulation and to record high-fidelity signals unlocks the visualization of the local neuromodulation of the multiunit biomarker. These findings demonstrate the potential of bidirectional high-resolution neural interfaces to investigate the mechanisms around DBS in preclinical models and suggest new avenues for the use of adaptive closed-loop operation based on electrophysiological biomarkers monitoring.

bioengineering↗