Biology subjects

Marty, A.

Publications and source records attributed to Marty, A..

5 recordsLinked to original sources

bioRxiv2024

Genetic evolution of keratinocytes to cutaneous squamous cell carcinoma

We performed multi-omic profiling of epidermal keratinocytes, precancerous actinic keratoses, and squamous cell carcinomas to understand the molecular transitions during skin carcinogenesis. Single-cell mutational analyses of normal skin cells showed that most keratinocytes have remarkably low mutation burdens, despite decades of sun exposure, however keratinocytes with TP53 or NOTCH1 mutations had substantially higher mutation burdens. These observations suggest that wild-type keratinocytes (i.e. without pathogenic mutations) are able to withstand high dosages of cumulative UV radiation, but certain pathogenic mutations break these adaptive mechanisms, priming keratinocytes for transformation by increasing their mutation rate. Mutational profiling of squamous cell carcinomas adjacent to actinic keratoses revealed TERT promoter and CDKN2A mutations emerging in actinic keratoses, whereas additional mutations inactivating ARID2 and activating the MAPK-pathway delineated the transition to squamous cell carcinomas. Surprisingly, actinic keratoses were often not related to their neighboring squamous cell carcinoma, indicating that collisions of unrelated neoplasms are common in the skin. Spatial variation in gene expression patterns was common in both tumor and immune cells, with high expression of checkpoint molecules at the invasive front of tumors. In conclusion, this study catalogues the key events during the evolution of cutaneous squamous cell carcinoma.

genomics↗

bioRxiv2024

Central Nervous System Control of breathing in Natural Conversational Turn-Taking

Discussion is a fundamental social activity requiring coordination of speech between interlocutors. Speech production is a complex human behaviour that involves several anatomo-physiological processes, including inspiration and expiration. The aim of the present study is to investigate the neurophysiological underpinnings of speech-related respiration events in conversational turn-taking. We made use of an existing corpus of natural conversations between a participant and its interlocutor (Human or Robot) focusing on synchronised (1) behavioural (conversation turn-taking), (2) respiratory (maxima of inspiration) and (3) neurophysiological (fMRI) data. Precisely timed conversation transcripts from 25 participants were used to categorise breathing maxima based on their timing relative to the participants speech onset. In agreement with the literature, the closest respiration time maximum to each speech turn occurred on average 200 ms prior to speech onset. The fMRI second-level contrast (pFWE < 0.05, extend k > 5 cm3) Resp+ (maximum respiration associated with speech) versus Resp-, exclusively masked to exclude speech related areas, revealed bilateral activations in the central sulcus, the brainstem and the cerebellum. The brainstem cluster comprises respiratory pattern generators, possibly the preBotzinger complex, that need to be inhibited to enslave breathing to speech production and not physiological needs, while the central sulcus cluster is likely to be located in the postcentral primary sensory cortex receiving upper torso inputs indicating that lungs are filled, and the cerebellum clusters could play a role in the timing of speech onset, 200 ms after a respiration maximum. These results show how cortical, cerebellar and brainstem coordinated control of breathing during conversational turn-taking is part of the intricate physiological mechanisms that contribute to natural communication dynamics.

neuroscience↗

bioRxiv2024

Molecular effects of indoor tanning

BackgroundTanning bed users have a significantly increased risk of melanoma, but it remains unclear how indoor tanning drives melanomagenesis. Tanning bed radiation is often thought of as a substitute for natural UV radiation despite differences in the maximum doses, UV content, body sites exposed, and patterns of melanoma that arise. MethodsTo better understand the epidemiologic trends and etiology of melanoma associated with tanning bed use, we described the patterns of melanoma in patients with quantifiable tanning bed usage and performed exome sequencing of 182 melanocytes from normal skin of a subset of these patients. ResultsTanning bed users were more likely than non-users to have melanoma on body sites with low cumulative levels of sun damage and were more likely to have multiple melanomas. The melanocytes in normal appearing skin from tanning bed users had higher mutation burdens, a higher proportion of melanocytes with pathogenic mutations, and distinct mutational signatures. These differences were most prominent over body sites that experience comparatively less exposure to natural sunlight. ConclusionsWe conclude that tanning bed radiation induces melanoma by increasing the mutation burden of melanocytes and by mutagenizing a broader field of melanocytes than are typically exposed to natural sunlight. The unique signatures of mutations in skin cells of tanning users may be attributable to the distinct spectra of radiation emitted from solariums.

genomics↗

bioRxiv2023

A maximum of two readily releasable vesicles per docking site at a cerebellar single active zone synapse

Recent research suggests that in central mammalian synapses, active zones contain several docking sites acting in parallel. Before release, one or several synaptic vesicles (SVs) are thought to bind to each docking site, forming the readily releasable pool (RRP). Determining the RRP size per docking site has important implications for short-term synaptic plasticity. Here, we take advantage of recently developed methods to count the number of released SVs at single glutamatergic synapses in response to trains of action potentials. In each recording, the number of docking sites was determined by fitting with a binomial model the number of released SVs in response to individual action potentials. After normalization with respect to the number of docking sites, the summed number of released SVs following a train of action potentials was used to estimate of the RRP size per docking site. To improve this estimate, various steps were taken to maximize the release probability of docked SVs, the occupancy of docking sites, as well as the extent of synaptic depression. Under these conditions, the RRP size reached a maximum value close to two SVs per docking site. The results indicate that each docking site contains two distinct SV binding sites that can simultaneously accommodate up to one SV each. They further suggest that under special experimental conditions, as both sites are close to full occupancy, a maximal RRP size of two SVs per docking site can be reached. More generally, the results validate a sequential two-step docking model previously proposed at this preparation.

neuroscience↗

bioRxiv2022

Prioritized docking of synaptic vesicles provided by a rapid recycling pathway

It is known that endocytosis of synaptic vesicles, and docking of these vesicles to their release sites, are regulated in a similar manner, but it has remained unclear whether the two processes are linked together mechanistically. To address this issue, we studied vesicular release during repeated trains of presynaptic action potentials. Synaptic responses decreased whenthe inter-train interval was shortened, indicating a gradual exhaustion of the recycling pool of vesicles, with a resting capacity of about 180 vesicles per active zone. This effect was partially counteracted by activation of a rapid recycling pathway that depended on the activation of myosin light chain kinase and that had a capacity of 200 vesicles per active zone. Vesicles arising from the rapid recycling route were preferentially docked in comparison with vesicles coming from an upstream pool, demonstrating a differential sorting of vesicles inside the readily releasable pool depending on their origin.

neuroscience↗