Biology subjects

Luciano, M.

Publications and source records attributed to Luciano, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Geometric confinement regulates ERK signaling dynamics and collective migration

Collective cell migration is a fundamental process in morphogenesis, tissue repair, cancer invasion, and frequently occurs under geometric confinement in vivo. However, how confinement interfaces with signaling pathways that coordinate collective motion remains poorly understood. Here, we confine migrating epithelial monolayers within adhesive microstripes of defined width and observe a progressive slow-down of collective migration with increasing spatial confinement. Combining biophysical modeling, live imaging of ERK activity, and pharmacological perturbations, we show that confinement increases tissue crowding while reducing cell and nuclear projected areas, thereby shifting epithelial tissues toward a mechanically compressed state associated with dampened ERK waves. Across conditions, migration speed scales with ERK signaling dynamics, which correlates with EGFR signaling as well as cell and nuclear projected areas, together serving as quantitative proxies for the confinement-imposed mechanical state. Pharmacological inhibition of ROCK restores cell spreading, ERK signaling, and migration under strong confinement, demonstrating that this state is reversible and governed by actomyosin contractility. Together, our results identify geometric confinement as a physical regulator of a contractility-dependent mechanochemical state that controls ERK signaling and collective migration in epithelial tissues.

biophysics↗

bioRxiv2026

Multiscale curvature modulates epithelial architecture and nuclear organization.

Curved geometries are a defining feature of epithelial tissues, yet how cells integrate curvature cues across spatial scales remains unclear. Here, we combined wavy hydrogels with inducible self-rolling substrates to readily and independently impose local and large-scale curvatures on epithelial monolayers, recapitulating key geometric features of bronchiolar epithelia. By controlling the orientation of local curvature relative to the large-scale curvature set by the tube axis, we show that multiscale curvature induces scale-dependent and anisotropic remodeling of cell shape, nuclear organization, and tissue thickness. In contrast, nuclei maintain a robust and conserved three-dimensional geometry, with curvature primarily regulating nuclear orientation rather than shape. This hierarchical induction of specific changes to the tissue architecture shows that multiscale curvature sensing is a fundamental physical principle governing epithelial architecture.

biophysics↗

bioRxiv2025

Electric field intensity modulates keratocyte migration without altering turning dynamics

Cell migration is a cornerstone of biological systems, enabling organisms to adapt to environmental stimuli and maintain homeostasis. Disruptions in this process can lead to functional impairment or system failure. In many cases, cells do not move randomly; instead, they migrate directionally in response to external cues, allowing them to perform essential biological functions. This directed movement is especially important in processes such as morphogenesis, cancer invasion, and wound healing. To unravel the complexities of directional cell migration, investigating natural guiding stimuli is crucial. Among these, electrical fields stand out as precise and physiologically relevant stimulus. Using a platform designed to apply programmable electric fields, the SCHEEPDOG device; we applied controlled electric field of varying intensities to keratocytes and quantitatively analyzed their migratory behavior. Our findings reveal that electric field stimulation not only induces robust directional migration but also enhances migration speed in an intensity-dependent manner. Additionally, cells initially moving in random directions gradually align with the field vector, with higher intensities accelerating the alignment. Intriguingly, while both speed and alignment time can be modulated through stimulation, the overall shape of migration trajectories remains unchanged. In other terms, for cells initially moving to the opposite direction of the field, the alignment is accompanied by making a turn and the size and shape of this turn is not affected by the magnitude of the electrical stimulation. Together, these results demonstrate that electrical stimulation can tune the speed and directional alignment of keratocyte migration without altering turning dynamics. These findings contribute to a deeper understanding of electrotaxis and offers new insights into how biophysical cues regulate cell migration in both physiological and pathological contexts.

biophysics↗

bioRxiv2025

Epigenome-wide association study meta-analysis of wellbeing

Wellbeing is associated with both behavioral phenotypes as well as several key life outcomes, such as health, employment, and coping with stressful events. These phenotypes associated with wellbeing could be potential indicators of differential epigenetic patterns between individuals that differ in their levels of wellbeing. We performed the largest epigenome-wide (EWAS) meta-analysis of wellbeing to date by combining whole blood DNA methylation data (Illumina 450k array) from 13 cohorts from Europe, Australia, and the USA (N = 10,757 participants). After correcting for smoking and BMI, no epigenome-wide significant methylation sites were identified. We tested whether a weighted methylation score (MS) based on leave-one-cohort-out EWAS meta-analysis summary statistics predicted wellbeing in an independent cohort, and whether prediction was significant over and above the polygenic score (PGS) for wellbeing. The MS was associated with wellbeing (variance explained=0.22%, p=0.03) and was no longer significant after adding the polygenic score (PGS; variance explained=0.43%, p=0.0046, MS; variance explained=0.07%, p=0.2842). We further compared DNA methylation levels in 16 pairs of monozygotic twins discordant for wellbeing. These analyses revealed no significant within-pair DNA methylation differences at the top-sites from the meta-analysis or in MS. Our results suggest that larger EWAS meta-analyses with uniform phenotype assessment are required to identify methylation sites associated with wellbeing.

genomics↗

bioRxiv2024

Lifetime brain atrophy estimated from a single MRI: measurement characteristics and genome-wide correlates

A measure of lifetime brain atrophy (LBA) obtained from a single magnetic resonance imaging (MRI) scan could be an attractive candidate to boost statistical power in uncovering novel genetic signals and mechanisms of neurodegeneration. We analysed data from five young and old adult cohorts (MRi-Share, Human Connectome Project, UK Biobank, Generation Scotland Subsample, and Lothian Birth Cohort 1936 [LBC1936]) to test the validity and utility of LBA inferred from cross-sectional MRI data, i.e., a single MRI scan per participant. LBA was simply calculated based on the relationship between total brain volume (TBV) and intracranial volume (ICV), using three computationally distinct approaches: the difference (ICV-TBV), ratio (TBV/ICV), and regression-residual method (TBV[~]ICV). LBA derived with all three methods were substantially correlated with well-validated neuroradiological atrophy rating scales (r = 0.37-0.44). Compared with the difference or ratio method, LBA computed with the residual method most strongly captured phenotypic variance associated with cognitive decline (r = 0.36), frailty (r = 0.24), age-moderated brain shrinkage (r = 0.45), and longitudinally-measured atrophic changes (r = 0.36). LBA computed using a difference score was strongly correlated with baseline (i.e., ICV; r = 0.81) and yielded GWAS signal similar to ICV (rg = 0.75). We performed the largest genetic study of LBA to date (N = 43,110), which was highly heritable (h2 SNP GCTA = 41% [95% CI = 38-43%]) and had strong polygenic signal (LDSC h2 = 26%; mean{chi} 2 = 1.23). The strongest association in our genome-wide association study (GWAS) implicated WNT16, a gene previously linked with neurodegenerative diseases such as Alzheimer, and Parkinson disease, and amyotrophic lateral sclerosis. This study is the first side-by-side evaluation of different computational approaches to estimate lifetime brain changes and their measurement characteristics. Careful assessment of methods for LBA computation had important implications for the interpretation of existing phenotypic and genetic results, and showed that relying on the residual method to estimate LBA from a single MRI scan captured brain shrinkage rather than current brain size. This makes this computationally-simple definition of LBA a strong candidate for more powerful analyses, promising accelerated genetic discoveries by maximising the use of available cross-sectional data.

genetics↗

bioRxiv2024

The actin cortex acts as a mechanical memory of morphology in confined migrating cells

Cell migration in narrow microenvironments is a hallmark of numerous physiological processes, involving successive cycles of confinement and release that drive significant morphological changes. However, it remains unclear whether migrating cells can retain a memory of their past morphological states, which could potentially enhance their navigation through confined spaces. By combining cell migration assays on standardized microsystems with biophysical modeling and biochemical perturbations, we demonstrate that local geometry governs these morphological switches, thereby facilitating cell passage through long and narrow gaps. We uncovered a long-term memory of past confinement events in migrating cells, with morphological states correlated across transitions through actin cortex remodeling. These findings suggest that mechanical memory in migrating cells plays an active role in their migratory potential in confined environments.

biophysics↗

bioRxiv2024

GenomicSEM Modelling of Diverse Executive Function GWAS Improves Gene Discovery

Previous research has supported the use of latent variables as the gold-standard in measuring executive function. However, for logistical reasons genome-wide association studies (GWAS) of executive function have largely eschewed latent variables in favour of singular task measures. As low correlations have traditionally been found between individual executive function (EF) tests, it is unclear whether these GWAS have truly been measuring the same construct. In this study, we addressed this question by performing a factor analysis on summary statistics from eleven GWAS of EF taken from five studies, using GenomicSEM. Models demonstrated a bifactor structure consistent with previous research, with factors capturing common EF and working memory-specific variance. Furthermore, the GWAS performed on this model identified 20 new genomic risk loci for common EF and 4 for working memory reaching genome-wide significance beyond what was found in the constituent GWAS, together resulting in 29 newly mapped EF genes. These results help to clarify the underlying genetic structure of EF and support the idea that EF GWAS are capable of measuring genetic variance related to latent EF constructs even when not using factor scores. Furthermore, they demonstrate that GenomicSEM can combine GWAS with divergent and non-ideal measures of the same phenotype to improve statistical power.

genetics↗

bioRxiv2023

The shared genetic architecture and evolution of human language and musical rhythm

Rhythm and language-related traits are phenotypically correlated, but their genetic overlap is largely unknown. Here, we leveraged two large-scale genome-wide association studies performed to shed light on the shared genetics of rhythm (N=606,825) and dyslexia (N=1,138,870). Our results reveal an intricate shared genetic and neurobiological architecture, and lay groundwork for resolving longstanding debates about the potential co-evolution of human language and musical traits.

genomics↗

bioRxiv2023

A minimal physical model for curvotaxis driven by curved protein complexes at the cell's leading edge

Cells often migrate on curved surfaces inside the body, such as curved tissues, blood vessels or highly curved protrusions of other cells. Recent in-vitro experiments provide clear evidence that motile cells are affected by the curvature of the substrate on which they migrate, preferring certain curvatures to others, termed "curvotaxis". The origin and underlying mechanism that gives rise to this curvature sensitivity are not well understood. Here, we employ a "minimal cell" model which is composed of a vesicle that contains curved membrane protein complexes, that exert protrusive forces on the membrane (representing the pressure due to actin polymerization). This minimal-cell model gives rise to spontaneous emergence of a motile phenotype, driven by a lamellipodia-like leading edge. By systematically screening the behaviour of this model on different types of curved substrates (sinusoidal, cylinder and tube), we show that minimal ingredients and energy terms capture the experimental data. The model recovers the observed migration on the sinusoidal substrate, where cells move along the grooves (minima), while avoiding motion along the ridges. In addition, the model predicts the tendency of cells to migrate circumferentially on convex substrates and axially on concave ones. Both of these predictions are verified experimentally, on several cell types. Altogether, our results identify the minimization of membrane-substrate adhesion energy and binding energy between the membrane protein complexes as key players of curvotaxis in cell migration.

biophysics↗

bioRxiv2023

General and specific patterns of cortical gene expression as substrates of complex cognitive functioning

Gene expression varies across the brain. This spatial patterning denotes specialised support for particular brain functions. However, the way that a given genes expression fluctuates across the brain may be governed by general rules. Quantifying patterns of spatial covariation across genes would offer insights into the molecular characteristics of brain areas supporting, for example, complex cognitive functions. Here, we use principal component analysis to separate general and unique gene regulatory associations with cortical substrates of cognition. We find that the region-to-region variation in cortical expression profiles of 8235 genes covaries across two major principal components : gene ontology analysis suggests these dimensions are characterised by downregulation and upregulation of cell-signalling/modification and transcription factors. We validate these patterns out-of-sample and across different data processing choices. Brain regions more strongly implicated in general cognitive functioning (g; 3 cohorts, total meta-analytic N = 39,519) tend to be more balanced between downregulation and upregulation of both major components (indicated by regional component scores). We then identify a further 41 genes as candidate cortical spatial correlates of g, beyond the patterning of the two major components (|{beta}| range = 0.15 to 0.53). Many of these genes have been previously associated with clinical neurodegenerative and psychiatric disorders, or with other health-related phenotypes. The results provide insights into the cortical organisation of gene expression and its association with individual differences in cognitive functioning.

neuroscience↗

bioRxiv2022

Geometry-driven migration efficiency of minimal cell clusters

The directed migration of epithelial cell collectives through coordinated movements plays a crucial role in various physiological and pathological processes and is increasingly understood at the level of large confluent monolayers. However, numerous processes rely on the migration of small groups of polarized epithelial clusters in complex environments, and their responses to external geometries remain poorly understood. To address this, we cultivated primary epithelial keratocyte tissues on adhesive microstripes, creating autonomous epithelial clusters with well-defined geometries. We showed that their migration efficiency is strongly influenced by the contact geometry, and the orientation of cell-cell contacts with respect to the direction of migration. To elucidate the underlying mechanisms, we systematically explored possible cell-cell interactions using a minimal active matter model. Our investigations revealed that a combination of velocity and polarity alignment with contact regulation of locomotion captures the experimental data, which we then validated via force and intracellular stress measurements. Furthermore, we predict that this combination of rules enables efficient navigation in complex geometries, which we confirm experimentally. Altogether, our findings provide a conceptual framework for extracting interaction rules governing the behavior of active systems interacting with physical boundaries, as well as designing principles for collective navigation in complex microenvironments.

biophysics↗

bioRxiv2021

The NLRP3/eIF2 axis drives cell cycle progression in acute myeloid leukemia

Aberrant activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome mediates numerous inflammatory diseases. Oncogenes can activate the NLRP3 inflammasome and thereby promote myeloproliferative neoplasia, suggesting a crucial role of NLRP3 in the malignant transformation of hematopoietic cells. Here, we show that bone marrow-derived mononuclear cells of AML patients display enhanced expression of NLRP3, IL-1{beta} and IL-18 and that high-level expression of NLRP3 is linked to poor survival of AML patients. Pharmacological and genetic inhibition of NLRP3 inflammasome activation attenuated cell proliferation of MOLM-13 AML cells in vitro. In vivo, genetic inhibition of NLRP3 in MOLM-13 AML cells resulted in reduced engraftment potential in xenografts, along with reduced splenomegaly and organ infiltration. Differential proteomic analysis revealed the eIF2 pathway as potential target of NLRP3 in AML, with a significant increase of eIF2 phosphorylation upon NLRP3 inhibition. NLRP3 inhibition also caused a strong decrease in cyclin - dependent kinases CDK4 and CDK6, accompanied by an upregulation of the CDK inhibitor p21 (CDKN1A) and a marked arrest of cell cycle progression in the G0/G1 phase, consistent with the role of eIF2 phosphorylation as negative cell cycle regulator. Taken together, we show that inhibition of the NLRP3 inflammasome reduces AML cell proliferation by promoting eIF2 phosphorylation, which in turn enhances the expression of cell cycle arrest genes such as p21. Thus, the study uncovers the NLRP3/eIF2 axis as new driver of AML proliferation and proposes a novel therapeutic treatment of AML by targeted inhibition of NLRP3 activation.

immunology↗

bioRxiv2020

A plant lipocalin is required for retinal-mediated de novo root organogenesis

Branching of root systems enables the exploration and colonization of the soil environment. In Arabidopsis roots, de novo organogenesis of lateral roots is patterned by an oscillatory mechanism called the root clock, which is dependent on metabolites derived from the {beta}-carotene pathway1, 2. Retinoids are {beta}-carotene-derived regulators of organogenesis in the animal kingdom. To determine if retinoids function in plant development, we conducted time-lapse imaging of a chemical reporter for retinoid binding proteins. We found that it oscillates with a comparable frequency to the root clock and accurately predicts sites of lateral root organogenesis. Exogenous application of retinal to wild-type plants is sufficient to induce root clock oscillations and lateral root organogenesis. A homology search yielded a potential Arabidopsis homolog, TEMPERATURE INDUCED LIPOCALIN (TIL) to vertebrate retinoid binding proteins. Genetic analysis indicates that TIL is necessary for normal lateral root development and a til mutant has decreased retinal sensitivity. TIL expression in a heterologous system conferred retinal binding activity, suggesting that it may directly interact with this molecule. Together, these results demonstrate an essential role for retinal and for plant retinal binding proteins in lateral root organogenesis.

plant biology↗

bioRxiv2020

Large-scale curvature sensing by epithelial monolayers depends on active cell mechanics and nuclear mechanoadaptation

While many tissues fold in vivo in a highly reproducible and robust way, epithelial folds remain difficult to reproduce in vitro, so that the effects and underlying mechanisms of local curvature on the epithelial tissue remains unclear. Here, we photoreticulated polyacrylamide hydrogels though an optical photomask to create corrugated hydrogels with isotropic wavy patterns, allowed us to show that concave and convex curvatures affect cellular and nuclear shape. By culturing MDCK epithelial cells at confluency on corrugated hydrogels, we showed that the substrate curvature leads to thicker epithelial zones in the valleys and thinner ones on the crest, as well as corresponding density, which can be generically explained by a simple 2D vertex model, leading us to hypothesize that curvature sensing could arise from resulting density/thickness changes. Additionally, positive and negative local curvatures lead to significant modulations of the nuclear morphology and positioning, which can also be well-explained by an extension of vertex models taking into account membrane-nucleus interactions, where thickness/density modulation generically translate into the corresponding changes in nuclear aspect ratio and position, as seen in the data. Consequently, we find that the spatial distribution of Yes associated proteins (YAP), the main transcriptional effector of the Hippo signaling pathway, is modulated in folded epithelial tissues according to the resulting thickness modulation, an effect that disappears at high cell density. Finally, we showed that these deformations are also associated with changes of A-type and B-type lamin expression, significant chromatin condensation and to lower cell proliferation rate. These findings show that active cell mechanics and nuclear mechanoadaptation are key players of the mechanistic regulation of epithelial monolayers to substrate curvature, with potential application for a number of in vivo situations.Competing Interest StatementThe authors have declared no competing interest.View Full Text

biophysics↗

bioRxiv2019

Common genetic variation indicates separate etiologies for periventricular and deep white matter hyperintensities

We conducted a genome-wide association meta-analysis of two ischemic white matter disease subtypes in the brain, periventricular and deep white matter hyperintensities (PVWMH and DWMH). In 26,654 participants, we found 10 independent genome-wide significant loci only associated with PVWMH, four of which have not been described previously for total WMH burden (16q24.2, 17q21.31, 10q23.1, 7q36.1). Additionally, in both PVWMH and DWMH we observed the previous association of the 17q25.1 locus with total WMH. We found that both phenotypes have shared but also distinct genetic architectures, consistent with both different underlying and related pathophysiology. PVWMH had more extensive genetic overlap with small vessel ischemic stroke, and unique associations with several loci implicated in ischemic stroke. DWMH were characterized by associations with loci previously implicated in vascular as well as astrocytic and neuronal function. Our study confirms the utility of these phenotypes and identifies new candidate genes associated only with PVWMH.

neuroscience↗

bioRxiv2019

Stratifying depression by neuroticism: revisiting a diagnostic tradition using GWAS data

Major depressive disorder and neuroticism share a large genetic basis. We sought to determine whether this shared basis could be decomposed to identify genetic factors that are specific to depression. We analysed two sets of summary statistics from genome-wide association studies of depression (from the Psychiatric Genomics Consortium and 23andMe) and compared them to GWAS of neuroticism (from UK Biobank). First, we used a pairwise GWAS analysis to classify variants as associated with only depression, with only neuroticism, or with both. Second, we estimated partial genetic correlations to test whether the depressions genetic link with other phenotypes was explained by shared overlap with neuroticism. We found evidence that most genetic variants associated with depression are likely to be shared with neuroticism. The overlapping common genetic variance of depression and neuroticism was negatively genetically correlated with cognitive function and positively genetically correlated with several psychiatric disorders. We found that the genetic contributions unique to depression, and not shared with neuroticism, were correlated with inflammation, cardiovascular disease, and sleep patterns. Our findings demonstrate that, while genetic risk factors for depression are largely shared with neuroticism, there are also non-neuroticism related features of depression that may be useful for further patient or phenotypic stratification.

genetics↗

bioRxiv2018

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3,337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc) -three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. CpG sites associated with hippocampus volume were significantly enriched within cancer-related genes and within regulatory elements containing the transcriptionally repressive histone H3K27 tri-methylation mark that is vital for stem cell fate specification. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

genomics↗

bioRxiv2018

Genetic Determinants of Cortical Structure (Thickness, Surface Area and Volumes) among Disease Free Adults in the CHARGE Consortium

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,822 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 161 genome-wide significant associations pointing to wnt/{beta}-catenin, TGF-{beta} and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

genetics↗