Biology subjects

Dempsey, B.

Publications and source records attributed to Dempsey, B..

6 recordsLinked to original sources

bioRxiv2024

A dynamic redox switch turns TRC40 into a chaperone protecting human cells against ATP-depleting, oxidative stress

Oxidative stress represents a major challenge for cellular proteostasis. The accumulation of reactive oxygen species, such as hydrogen peroxide, impairs the fidelity of protein biosynthesis and causes non-specific oxidative protein modifications and aggregation. This situation is further aggravated by the oxidative stress-mediated drop in cellular ATP levels, which reduces the activity of ATP-dependent chaperones and proteases. We now demonstrate that to cope with oxidative unfolding stress, human cells rely on the moonlighting function of TRC40, which turns from an ATP-dependent targeting factor into an ATP-independent chaperone upon oxidation. Controlled by a highly conserved redox switch, oxidized TRC40 forms chaperone-active tetramers and high-molecular complexes which prevent the aggregation of unfolding proteins. Acute oxidative stress leads to the reversible formation of distinct TRC40 foci, associated with the canonical chaperones Hsp70 and Hsp110, suggesting a role of these stress-induced structures in recovering and sorting aberrant proteins. Consistently, we discovered that TRC40 is essential upon ATP-depleting, oxidative stress conditions to counteract the accumulation of mis- and unfolded proteins, which are rapidly cleared in an TRC40-dependent manner. Our data reveal that TRC40 is an integral part of protein quality control and support its role as a triaging factor in cellular proteostasis.

cell biology↗

bioRxiv2024

A PHOX2b+ PONTINE NUCLEUS ESSENTIAL FOR INGESTION.

The first phase of feeding consists in acquiring solid foods from the environment by biting, and their preparation for swallowing by chewing. These actions require the precise coordination of tens of orofacial muscles for the jaw and tongue. The siege for this motor patterning is known to be in the reticular formation, a complex and poorly mapped region of the hindbrain, but the neuron groups involved are still elusive. Here, we characterize a group of reticular interneurons located in the supratrigeminal area that express the homeodomain transcription factor Phox2b. This nucleus -- Sup5Phox2b-- is premotor to both jaw-closing and jaw-opener motoneurons and receives direct input from cranial sensory afferents, motor cortex and satiation related nuclei. Its activity differentially tracks lapping, biting and chewing movements, suggesting its involvement in the elaboration of distinct orofacial motor patterns in vivo. Acute global activation or inhibition of Sup5Phox2bby optogenetics both interrupt volitional feeding sequences. Thus, Sup5Phox2bis an obligatory subcortical node, topologically and genetically defined, in the neural circuits that control the oral phase of feeding. TeaserA genetically defined cluster of neurons in the hindbrain is an essential relay for biting and chewing food.

physiology↗

bioRxiv2023

The pelvic organs receive no parasympathetic innervation

The pelvic organs (bladder, rectum and sex organs) have been represented for a century as receiving autonomic innervation from two pathways -- lumbar sympathetic and sacral parasympathetic -- by way of a shared relay, the pelvic ganglion, conceived as an assemblage of sympathetic and parasympathetic neurons. Using single cell RNA sequencing, we find that the mouse pelvic ganglion is made of four classes of neurons, distinct from both sympathetic and parasympathetic ones, albeit with a kinship to the former, but not the latter, through a complex genetic signature. We also show that spinal lumbar preganglionic neurons synapse in the pelvic ganglion onto equal numbers of noradrenergic and cholinergic cells, both of which therefore serve as sympathetic relays. Thus, the pelvic viscera receive no innervation from parasympathetic or typical sympathetic neurons, but instead from a divergent tail end of the sympathetic chains, in charge of its idiosyncratic functions.

neuroscience↗

bioRxiv2021

An executive center for the intake of liquids

It has long been known that orofacial movements for feeding can be triggered, coordinated, and often rhythmically organized at the level of the brainstem, without input from higher centers. We uncover two nuclei that can organize the movements for ingesting fluids in mammals. These neuronal groups, defined by unique transcriptional codes and developmental origins, IRtPhox2b and Peri5Atoh1, are located, respectively, in the intermediate reticular formation of the medulla and around the motor nucleus of the trigeminal nerve. They are premotor to all jaw-opening and tongue muscles. Stimulation of either, in awake animals, opens the jaw, while IRtPhox2b alone also protracts the tongue. Moreover, stationary stimulation of IRtPhox2b entrains a rhythmic alternation of tongue protraction and retraction, synchronized with jaw opening and closing, that mimics lapping. Finally, fiber photometric recordings show that IRtPhox2b is active during volitional lapping. Our study identifies one of the long hypothesized subcortical nuclei underpinning a stereotyped feeding behavior.

neuroscience↗

bioRxiv2021

A novel reticular oscillator in the brainstem synchronizes neonatal crying with breathing

Human speech can be divided into short, rhythmically-timed elements, similar to syllables within words. Even our cries and laughs, as well as the vocalizations of other species, are periodic. However, the cellular and molecular mechanisms underlying the tempo of mammalian vocalizations remain unknown. Here we describe rhythmically-timed neonatal mouse vocalizations that occur within single breaths, and identify a brainstem node that structures these cries, which we name the intermediate reticular oscillator (iRO). We show that the iRO acts autonomously and sends direct inputs to key muscles in order to coordinate neonatal vocalizations with breathing, as well as paces and patterns these cries. These results reveal that a novel mammalian brainstem oscillator embedded within the conserved breathing circuitry plays a central role in the production of neonatal vocalizations.

neuroscience↗

bioRxiv2020

Everything Under Control? Comparing Knepp Estate rewilding project with 'traditional nature conservation

Rewilding is an increasingly prominent concept in conservation, but one that has attracted controversy. Debate frequently focuses on control, with rewilding presented as reducing human control of nature. Opposition to rewilding often stems from a perceived lack of control - and associated perception of increased risk and uncertainty. I explore the concept of control in conservation. I identify that control is not a simple, linear concept, but consists of multiple dimensions. Using a lens of control, I compare two ethnographic case studies: the Sussex Wildlife Trusts Old Lodge nature reserve; and Knepp Estate, one of the most influential rewilding projects in the UK. These sites ostensibly represent high-control and low-control examples of conservation. I outline how Old Lodge does not exert precise control in all respects, but rather involves elements of uncertainty and negotiation. I describe how Knepps model of rewilding reduces control in some dimensions but increases it in others. I conclude that, while Knepps rewilding does represent a significant conceptual departure from traditional conservation, it should not be characterised simplistically as an approach that reduces control. Based on this analysis, I argue that reduction of control should not be assumed to underpin the concept of rewilding. Rather, there is interplay between different control dimensions that combine to form different configurations of control. With this understanding, debate about rewilding - and conservation more broadly - can avoid simplistic characterisations of reducing control and become instead an active discussion of what configuration of control is desired. This analysis could be seen negatively by those who argue that Knepps version of rewilding does not sufficiently reduce human control of nature. In contrast, Knepps approach can be seen positively as opening new conceptual space while retaining human involvement. It supports the argument that versions of rewilding can be legitimate, innovative components of plural conservation strategies.

ecology↗