Biology subjects

Bernat, A.

Publications and source records attributed to Bernat, A..

7 recordsLinked to original sources

bioRxiv2025

XPC loss-of-function triggers melanomagenesis through CDKN2A downregulation

We identified a novel XPC variant, c.2420+5G>A (XPCvar), in siblings with multiple melanomas, inherited alongside c.779+1G>T, which results in an absent or disrupted protein. However, they did not exhibit significantly higher nucleotide excision repair (NER) deficits compared to their unaffected parents, suggesting an NER-independent tumor suppressor function for XPC. XPC knockdown increased cell proliferation and tumorigenicity in vitro without affecting NER. Single-cell RNA sequencing revealed lower Cdkn2a in Xpcvar/var mouse melanocytes. Additionally, XPC knockdown downregulated CDKN2A in vitro. Furthermore, patient fibroblasts showed decreased p16INK4a, which was rescued by XPC overexpression. ChIP-PCR and luciferase assays confirmed XPC binding to the CDKN2A promoter, initiating transcription. Premature stop codon read-through, with gentamicin, restored XPC and p16INK4A in patient fibroblasts. These suggest that XPC regulates CDKN2A and XPC loss might promote melanomagenesis by downregulating CDKN2A, independent of its NER function. We provide preclinical evidence for potential preventive and/or therapeutic strategies for similarly affected individuals. STATEMENT OF SIGNIFICANCECharacterizing a novel XPC variant identified in patients with melanoma revealed a non-canonical role for XPC in regulating CDKN2A transcription. XPC binding to the CDKN2A promoter is crucial for CDKN2A expression and might suppress melanomagenesis. This expands our understanding of melanomagenesis and suggests potential therapies targeting XPC-mediated regulation of CDKN2A.

cancer biology↗

bioRxiv2025

Measuring the Strength of Spatial Sorting

Empirical work suggests that spatial sorting--a mechanism of evolutionary change fueled by spatial assortment of phenotypes--may lead to phenotypic shifts on ecological timescales. However, we currently lack theoretical tools to measure the strength of spatial sorting, as we do to measure the strength of natural selection. To address this gap, we present a quantitative genetics model and identify an evolutionary parameter in the model to measure the strength of spatial sorting. This parameter, the standardized sorting gradient, is structurally akin to the standardized selection gradient, commonly used to measure the strength of natural selection. To show the utility of our approach, we analyzed wing-morphology data of soapberry bugs (Jadera haematoloma) recolonizing flooded habitats extirpated by a hurricane. We found that the estimated strength of spatial sorting ranked in the top ten percentile of standardized selection gradients documented in the scientific literature. Our results underscore that, like natural selection, spatial sorting, too, can yield rapid evolution after extreme events.

evolutionary biology↗

bioRxiv2023

A rise in double-strand breaks sensitizes tumours to oxidative metabolism inhibitors

ABSTRACTDouble strand brakes (DSB) accumulate in cellular DNA as a result of deficiencies in homologous recombination repair systems, such as mutations in BRCA genes, or upon antitumoral treatments. In the present study we show that the accumulation of DSB, regardless of its origins, leads to a shift towards oxidative metabolism. We have identified that DSB-induced reactive oxygen species (ROS) promote the activation of NRF2 which downregulates the glycolytic transcription factor HIF-1. HIF-1 inhibition is a key step in this metabolic shift, because leads to the reduction of PDHK1 levels and the consequential activation of pyruvate dehydrogenase, a mitochondrial gatekeeper of cellular metabolism, promoting this metabolic shift. Remarkably, after the induction of DSBs, the tumour is more sensitive to the inhibition of oxidative metabolism since both treatments synergize in vivo, resulting in reduced tumour growth. Therefore, we demonstrate a significant feedback between DSBs induction and cancer cell metabolism that ultimately limits the cells potential for metabolic plasticity, hence sensitizing it to the action of counteracting drugs.

cancer biology↗

bioRxiv2022

Dispersal-behavioral plasticity within an insect-host system undergoing human-induced rapid environmental change (HIREC)

As environments change, often drastically, due to human activities, dispersal-behavioral plasticity can become a key mediator of metapopulation connectivity and the interactions between an individual and its altered environment. Our goal was to investigate the traits and ecological processes that affect plastic dispersal responses within an insect-host system undergoing human-induced rapid evolutionary change (HIREC). Since the 1960s, populations of the red-shouldered soapberry bug from Florida, USA, originally feeding on the seeds of Cardiospermum corindum on the islands, quickly adapted to feeding on an invasive, ornamental tree, Koelreuteria elegans, on the mainland, which led to host-specific wing polyphenism. Here, we measured the morphology of >3,500 soapberry bugs field collected from 2013 to 2020 and the flight performance of 378 total soapberry bugs tested in a flight mill during Fall 2019 and Winter 2020. Flight tests showed females and mainland natives exhibited variable flight responses mediated by mass, while males were consistent, wing-dependent flyers. However, historical specimens showed annual rises in flightless morphs for males and dwindling wing-to-body sizes for island natives since 2013. Despite uncertain future fitness consequences, plasticity could help predict mobility character and agent dispersal behavior and ultimately help identify whether recent trends signal adjustment or maladaptation to HIREC.

ecology↗

bioRxiv2022

Charting the Spatial Landscape of Cancer Hallmarks

Tumors are complex ecosystems with dozens of interacting cell types. The concept of Cancer Hallmarks distills this complexity into a set of underlying principles that govern tumor growth. Here, we exploit this abstraction to explore the physical distribution of Cancer Hallmarks across 63 primary untreated tumors from 10 cancer types using spatial transcriptomics. We show that Hallmark activity is spatially organized-with 7 out of 13 Hallmarks consistently more active in cancer cells than within the non-cancerous tumor microenvironment (TME). The opposite is true for the remaining six Hallmarks. Additionally, we discovered that genomic distance between tumor subclones correlates with differences in Cancer Hallmark activity, even leading to clone-Hallmark specialization in some cases. Finally, we demonstrate interdependent relationships between Cancer Hallmarks at the junctions of TME and cancer compartments. In conclusion, including the spatial dimension, particularly through the lens of Cancer Hallmarks, can improve our understanding of tumor ecology. SignificanceWe explored Cancer Hallmarks in 63 primary untreated tumors from 10 cancer types using spatial transcriptomics. This study unveiled spatial patterns in Hallmark activity, with some being more active in cancer cells and others in the non-cancerous tumor environment. Genomic distance impacted Hallmark activity, and we identified interdependencies at the TME-cancer junctions, improving our understanding of tumor ecology.

cancer biology↗

bioRxiv2020

Neural stem cells restore motor and cognitive function in a macaque model of Parkinson's disease

Parkinsons disease (PD) evolves over an extended and variable period in humans; several years prior to the onset of classical motor symptoms, cognitive deficits as well as sleep and biological rhythm disorders develop and worsen with disease progression, significantly impacting the quality of life of patients. The gold standard MPTP macaque model of PD recapitulates the progression of motor and non-motor symptoms over contracted periods of time. Here, this multidisciplinary and multiparametric study follows, in five animals, the steady progression of motor and non-motor symptoms and describes their reversal following bilateral grafts of neural precursors in diverse functional domains of the basal ganglia. Results show unprecedented recovery from cognitive symptoms in addition to a strong clinical motor recuperation. Both motor and cognitive recovery and partial circadian rhythm recovery correlate with the degree of graft integration into the host environment as well as with in-vivo levels of striatal dopaminergic innervation and function. Given inter-individuality of disease progression and recovery the present study underlines the importance of longitudinal multidisciplinary assessments in view of clinical translation and provides empirical evidence that integration of neural precursors following transplantation efficiently restores function at multiple levels in parkinsonian non-human primates. One Sentence SummaryEmpirical evidence that cell therapy efficiently reverts cognitive and clinical motor symptoms in the non-human primate model of Parkinsons disease.

neuroscience↗

bioRxiv2020

Reframing Fouquieria splendens in its larger environmental and ecological context: Effect of topography and interspecific neighbors on ocotillo morphology and distribution

Fouquieria splendens is a stem-succulent native to the Chihuahuan, Mojave, and Sonoran Deserts that spans Mexico and the American Southwest. It is well-known for its variable morphology, the underlying reason for which remains incompletely understood. Here, we attempt to quantify the effect of topographic and interspecific factors on F. splendens morphology and distribution. To this end, we measured 27 ocotillos located in the Organ Pipe Cactus National Monument within the Sonoran Desert during June of 2019. We also quantified the spatial distribution of interspecific neighbors relative to F. splendens within two topographically different sites: a bajada gradient and a plain. Using ocotillo morphology, the distances to the nearest neighbors of ocotillos, and hydrographic data extracted from the National Hydrography Dataset, we demonstrate 1) the effect of major interspecific neighbors, i.e. shrubs and cacti, on ocotillo morphology; 2) the effect of elevation on intraspecific spacing as individuals compete for limited space; and 3) a trade-off between height and number of branches. This places F. splendens morphology in its larger environmental and ecological context, highlighting the importance of individual traits and associated trade-offs among traits affected by topography and interspecific neighbors. By examining the ocotillo in a multi-species community and diverse landscape, this study provides empirical insight into a wider range of factors contributing to the variation in F. splendens morphology and spacing.

ecology↗