Biology subjects

Cowburn, A. S.

Publications and source records attributed to Cowburn, A. S..

3 recordsLinked to original sources

bioRxiv2025

A Geometrically Transient Material for Bioelectronic Implants

The outstanding barrier properties of skin make it difficult to obtain reliable physiological information (especially chemical) without the use of implantable bioelectronic sensing devices to directly access the internal biology. The clinical utility of bioelectronic implants however, hinges on a key geometrical optimization problem: devices must scale-down in size to reduce surgical invasiveness while also creating enough space to integrate electronics for wireless power delivery, data exchange, and electrical/electrochemical monitoring. Here, we present a minimally invasive bioelectronic implant with a transient geometry that can be inserted subcutaneously and measures important markers, such as pH, temperature, cardiac and respiratory activity, and levels of lithium, an important element for medical applications. To produce this new class of minimally invasive and foldable implantable sensors, we developed a fabrication method that works with highly flexible substrates to enable multiple-fold miniaturization during implantation. After implantation, the implant autonomously unfolds back to its planar form for continuous wireless operation. We demonstrate the key concepts concerning implantation, operation, and removal through extensive in vitro, ex vivo, and in vivo animal experiments. Our approach allows for robust multiplexed monitoring using quick and suture-free insertion procedures and may provide a unique advantage in the transition towards personalized health profiles.

bioengineering↗

bioRxiv2023

ARF6 as a novel activator of HIF-2alpha in pulmonary arterial hypertension

ADP-ribosylation factor 6 (ARF6), a GTPase associated with cancer metastasis, is activated in the lung endothelium in pulmonary arterial hypertension (PAH). To identify ARF6-regulated pathways relevant to PAH, we performed a state-of-the-art proteomic analysis of human pulmonary artery endothelial cells (HPAECs) overexpressing the wildtype, constitutively active, fast-cycling and dominant negative mutants of ARF6. The analysis revealed a novel link of ARF6 with hypoxia-inducible factor (HIF), in addition to endocytotic vesicle trafficking, cell proliferation, angiogenesis, oxidative stress and lipid metabolism. Active ARF6 markedly increased expression and activity of HIF-2, critical in PAH, with HIF-1 relatively unaffected. Hypoxic ARF6 activation was a prerequisite for HIF-2 activation and HIF-dependent gene expression in HPAECs, PAH blood-derived late outgrowth endothelial colony forming cells (ECFCs) and hypoxic mouse lungs in vivo. A novel ARF6 inhibitor, chlortetracycline (CTC), reduced hypoxia-induced HIF-2 activation, proliferation and angiogenesis in HPAECs and reduced HIF-2 expression in lung and heart tissues of hypoxic mice. PAH ECFCs showed elevated expression and activity of ARF6 and HIF2, which was attenuated by CTC. Oral CTC attenuated development of PH in chronically hypoxic mice. In conclusion, we are first to demonstrate a key role of ARF6 in the regulation of HIF-2 activation in vitro and in vivo and show that HIF-2, a master-regulator of vascular remodelling in PAH, can be targeted by a clinically approved antibiotic chlortetracycline.

cell biology↗

bioRxiv2018

HIF-2α is essential for carotid body development and function

Mammalian adaptation to oxygen flux occurs at many levels, from shifts in cellular metabolism to physiological adaptations facilitated by the sympathetic nervous system and carotid body (CB). Interactions between differing forms of adaptive response to hypoxia, including transcriptional responses orchestrated by the Hypoxia Inducible transcription Factors (HIFs), are complex and clearly synergistic. We show here that there is an absolute developmental requirement for HIF-2a, one of the HIF isoforms, for growth and survival of oxygen sensitive glomus cells of the carotid body. The loss of these cells renders mice incapable of ventilatory responses to hypoxia, and this has striking effects on processes as diverse as arterial pressure regulation, exercise performance, and glucose homeostasis. We show that the expansion of the glomus cells is correlated with mTORC1 activation, and is functionally inhibited by rapamycin treatment. These findings demonstrate the central role played by HIF-2a in carotid body development, growth and function.

bioinformatics↗