Biology subjects

Morelli, L.

Publications and source records attributed to Morelli, L..

At least 19 recordsLinked to original sources

bioRxiv2026

A generative network model reveals hierarchical structural memory guiding post-mitotic 3D genome inheritance

How three-dimensional (3D) genome organization is reestablished after mitosis to preserve gene regulatory programs and cell identity remains unresolved. We asked whether mitotic chromosome architecture contributes to cellular memory by preserving structural information while maintaining the flexibility required for cellular adaptation. Here we introduce HiCONA, a generative Bayesian framework that infers hierarchical genome organization and quantifies the structural contribution of individual interactions through an Entropy Impact Score. HiCONA resolves genome organization across multiple scales, revealing structure-defining interaction patterns underlying chromatin architecture, independently of experimental modality. We identify structurally impactful chromatin interactions retained during mitosis delineating distinct trajectories of post-mitotic genome reassembly. These mitotically preserved interactions are enriched for active, transcriptionally competent regulatory elements, consistent with a cis-encoded architectural memory subsequently remodeled by trans-acting regulators. Together, our findings suggest that molecular information retained on mitotic chromosomes guides structural trajectories, providing an architectural basis for epigenetic memory and post-mitotic genome inheritance.

genomics↗

bioRxiv2026

Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder caused by loss-of-function mutations in the MECP2 gene and characterized by profound impairments in neuronal maturation and synaptic connectivity. Increasing evidence indicates that astrocyte dysfunction contributes to RTT pathogenesis through non-cell-autonomous mechanisms, although the molecular pathways underlying defective astrocyte-neuron communication are only partially understood. Astrocytes are the primary source of cholesterol in the brain and support neuronal maturation and synaptic function by supplying cholesterol through ApoE-containing lipoproteins. Although alterations in brain cholesterol metabolism have been reported in RTT, the underlying cellular mechanisms and their functional consequences remain poorly investigated. Here, we studied cholesterol homeostasis in Mecp2 knock-out (KO) astrocytes and its impact on neuron-astrocyte communication. Mecp2 KO astrocytes exhibited reduced nuclear localization of the transcriptional regulator Srebp2, together with the downregulation of genes involved in cholesterol biosynthesis and transport. These molecular alterations were associated with intracellular cholesterol and desmosterol accumulation, reduced Abca1 expression and defective ApoE lipidation, despite preserved ApoE expression and cholesterol secretion. Importantly, similar alterations were detected in acutely isolated astrocytes and in the cerebral cortex of Mecp2 deficient mice, demonstrating that impaired cholesterol homeostasis extends beyond in vitro models. Functionally, cholesterol supplementation of astrocyte-conditioned medium rescued the synaptic defects induced in wild-type neurons by Mecp2 KO astrocytes. Moreover, cholesterol treatment restored pre- and post-synaptic density, as well as axon initial segment length in Mecp2 heterozygous (HET) neurons. Together, these findings identify defective astrocyte-to- neuron cholesterol trafficking as a key mechanism contributing to neuronal dysfunction in RTT and suggest that strategies aimed at restoring cholesterol functional availability might represent a promising therapeutic avenue for RTT.

neuroscience↗

bioRxiv2025

Preservation and remodelling of chloroplast lipids in photosynthetic sea slug host cells

The capacity to retain long-term functional algal chloroplasts within animal cells is a singular trait of some Sacoglossa sea slugs. The stolen chloroplasts (kleptoplasts) confer photosynthetic capacity to the host. This study investigated how chloroplast lipidomes from two macroalgae (Acetabularia acetabulum and Bryopsis sp.) are modified after sequestration by the photosynthetic sea slugs Elysia crispata, Elysia viridis, and Elysia timida. Pigments were analysed by HPLC, and lipidomic profiling of chloroplasts (glycolipids, betaine lipids, phytosterols) was conducted using C18-LC-MS/MS. Kleptoplasts retain intact algal pigment profile. Glycolipid signatures in sea slug tissues closely resembled those of their algal donors, although shifts in relative abundances suggest remodelling of plastidial membranes, potentially affecting kleptoplast morphology, particularly membrane curvature and stability. In contrast, betaine lipid composition differed markedly between sea slugs and algal donors, with major betaine species common to all sea slugs. Phytosterol composition was better preserved in sea slugs feeding on Bryopsis sp. than on A. acetabulum. This study demonstrated that kleptoplast lipidomes maintain a strong algal identity but undergo selective modifications within the animal host. This remodelling likely optimizes membrane architecture to support long-term stability and photosynthetic functionality within the hosts cellular environment, facilitating the integration and performance of sea slug kleptoplasts. HighlightThe lipid profiles of photosynthetic sea slugs resemble the algal donors chloroplasts. However, alterations in glycolipid composition suggest that the molecular architecture of kleptoplasts is modulated by the host cells.

biochemistry↗

bioRxiv2025

Repurposing the diatom periplastidial compartment for heterologous terpenoid production

Diatoms are promising microorganisms to provide sustainable routes for photosynthetic terpenoid production from CO2, yet their potential for compartmentalized engineering remains largely unexplored. Here, we systematically profiled the biosynthetic capacity of Phaeodactylum tricornutum by targeting representative synthases for hemi, mono, sesqui, and tetraterpenoids to the cytosol, chloroplast, and periplastidial compartment (PPC). This comprehensive analysis revealed that all major prenyl phosphate precursors, DMAPP, GPP, FPP, and GGPP, are accessible in all compartments, including in the PPC and can sustain heterologous flux without major physiological penalties, although production efficiency varies across compartments and product classes. By determining precursor availability, we propose the diatom PPC as a minimal engineerable organelle directly interfaced with a eukaryotic chloroplast. Moreover, we highlight its utility as a unique interface to investigate metabolic exchange between the MVA and MEP pathways. These findings provide a systematic framework for compartment-specific terpenoid engineering in diatoms and open new opportunities for modular pathway assembly and synthetic biology in photosynthetic eukaryotes.

synthetic biology↗

bioRxiv2025

Iterative and modular expression of Botryococcus braunii genes enhances isoprenoid production in the diatom Phaeodactylum tricornutum

Isoprenoids are essential natural compounds with high structural and functional diversity. Among them, carotenoids and triterpenoids such as squalene have high biotechnological value but remain challenging to produce sustainably. The green microalga Botryococcus braunii synthesizes large amounts of triterpenoids through specialized methylerythritol phosphate (MEP) pathway configurations involving distinct 1-deoxy-D-xylulose-5-phosphate synthase (DXS) isoforms, a bifunctional squalene synthase (SQS) and squalene synthase-like (SSL) enzymes working together for the synthesis of the compound. However, its slow growth limits industrial application. In this work, we established the fast-growing diatom Phaeodactylum tricornutum as a heterologous chassis for terpenoid production using a synthetic biology Design-Build-Test-Learn (DBTL)-based approach. Episomal uLoop assembly enabled rapid expression and evaluation of B. braunii DXS and SQS variants, enhancing precursor flux and resulting in the co-accumulation of squalene and carotenoids. This work demonstrates the functional transfer of specialized algal terpenoid enzymes into a tractable diatom host and highlight P. tricornutums potential as a versatile platform for sustainable, high-value isoprenoid biosynthesis.

synthetic biology↗

bioRxiv2025

Dysregulation of energy metabolism and calcium homeostasis in iPSC-derived neurons carrying Presenilin-1 M146L gene mutation

Impaired cellular activities, particularly in highly active cells such as neurons, are primarily supported by metabolic abnormalities and failures in Ca{superscript 2} homeostasis. Here, we provide an integrative analysis of human iPSC-derived neurons (iNs) carrying the Presenilin-1 M146L gene mutation (PS1M146L) and control cells (PS1control). PS1M146L iNs exhibited abnormal Ca{superscript 2} dynamics, a significant increase in key parameters of mitochondrial respiration, and higher intracellular ROS levels. KCl-evoked depolarisation was significantly lower in PS1M146L, suggesting a failure in maintaining the electrochemical gradient across the plasma membrane. Following thapsigargin stimulation, mitochondrial Ca{superscript 2} levels ([Ca{superscript 2}]m) were significantly reduced in PS1M146L, while [Ca{superscript 2}]m did not differ significantly between genotypes after treatment with bradykinin, suggesting that impairments in the [Ca{superscript 2}]m homeostasis are particularly evident under stress conditions and do not impact the 1,4,5-triphosphate (IP3) pathway. Since iNs of both genotypes were sensitive to the MCU-1 inhibitor, the deficits observed in PS1M146L could be the consequence of impairments in the ER-mitochondria contacts. Our results illustrate the utility of iNs carrying PS1 mutations in understanding how human neurons alter relevant pathways before neurodegeneration.

neuroscience↗

bioRxiv2025

Colitis-primed circulating T cells drive small intestinal barrier function through Nod2, microbiota and myosin light chain kinase-dependent mechanisms

Inflammatory bowel diseases (IBD), including Crohns disease (CD) and ulcerative colitis (UC), are characterized by intestinal inflammation and barrier dysfunction. While disruption of the intestinal barrier contributes to the pathogenesis of IBD, yet how colonic inflammation alters small intestinal homeostasis remains poorly defined. Here, we demonstrate that three models of colitis, including 2,4,6-Trinitrobenzenesulfonic acid (TNBS), Dextran Sulfate Sodium (DSS), and oxazolone, induce paracellular barrier dysfunction in the small intestine, with model-specific immune profiles. Th1/Th17-skewed responses (TNBS and DSS) were associated with microbiota-dependent upregulation of myosin light chain kinase (MLCK), ROR{gamma}t CD4 T cell expansion, and elevated expression of Nod2, which was not observed under Th2-dominant (oxazolone) conditions. Inhibition of MLCK restored barrier function and suppressed inflammation in a CD4 T cell-dependent manner. Using Nod2-deficient and 2939insC mutant mice, we showed Nod2 as a critical regulator of small intestinal permeability during colitis. Bone marrow chimeras revealed compartment-specific roles of Nod2, with non-hematopoietic Nod2 sufficient to preserve epithelial integrity, while hematopoietic Nod2 expression is required to limit cytokine-mediated inflammation. Moreover, MLCK inhibition ameliorated intestinal lesions only in mice with Nod2 deficiency in the hematopoietic compartment. Finally, microbiota transfer experiments ruled out a causal role for dysbiosis in driving small intestinal permeability defects in Nod2-deficient mice. These findings uncover a Nod2-MLCK-CD4 T cell axis linking colonic inflammation to small intestinal barrier dysfunction and highlight distinct immune-epithelial-microbial mechanisms shaping intestinal homeostasis during colitis. Graphical AbstractCirculating ROR{gamma}t Foxp3- CD4 T cells from mice with TNBS- or DSS-induced colitis increase small intestinal permeability by promoting cytokine secretion that enhances MLCK activity. This effect is attenuated by Nod2 activation. Specifically, Nod2 expression in hematopoietic cells reduces cytokine secretion and permeability, while activation of Nod2 in non-hematopoietic cells alone is sufficient to prevent increased permeability by directly regulating MLCK activity, independently of cytokine influence. Moreover, the absence of Nod2 is associated with inflammatory lesions in the small intestine of TNBS-treated mice.

immunology↗

bioRxiv2025

Dual-targeting strategy to repurpose Cetuximab with HFn nanoconjugates for immunotherapy of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a highly aggressive and treatment-resistant malignancy, characterized by the lack of targeted therapies and poor clinical outcomes. Here, we present a dual-targeting strategy combining the anti-EGFR monoclonal antibody Cetuximab (CTX) with H-ferritin (HFn), a nanoparticle targeting transferrin receptor 1 (TfR1), for potential immunotherapy in CTX-resistant tumors. The HFn-CTX nanoconjugate exhibited favorable biophysical properties, including a hydrodynamic size of <30 nm, and significantly enhanced antibody-dependent cellular cytotoxicity (ADCC) in TNBC spheroids compared to CTX alone. Conversely, glioblastoma spheroids did not exhibit comparable reactivity. This effect correlated with elevated cell-surface EGFR expression and plasma-membrane lingering of the nanoconjugate in TNBC cells, facilitating robust immune activation. Biodistribution studies showed selective accumulation of the HFn-CTX nanoconjugate in TNBC tumors in vivo. These findings highlight the potential of HFn-CTX nanoconjugates to repurpose CTX for refractory cancers that express EGFR at high levels like TNBC, leveraging dual-receptor targeting to amplify immune-mediated cytotoxicity and overcome resistance.

biochemistry↗

bioRxiv2025

Metastatic cell plasticity is maintained by SOX9 function during mitosis in breast cancer

Disseminated tumor cells (DTCs) contribute to metastasis formation by adapting to the hostile environmental conditions encountered at the seeded secondary organs. This phenotypic plasticity is supported by the epigenetic reprogramming of cis-regulatory elements (CREs), representing a hallmark of metastatic cells. DTCs can enter a reversible state of cancer dormancy, resulting from their ability to enter quiescence after mitosis and escape immune surveillance. In this respect, mitosis may represent a window of opportunity to increase DTCs fitness by priming CREs, ensuring the reactivation of a dormancy-related transcriptional program while preserving the epigenetic information. By profiling the chromatin changes occurring during the early steps of mitosis, we found that DTCs experience fluctuations in chromatin accessibility at CREs, which are bookmarked by pro-metastatic TFs. Among these, the pro-dormancy TF SOX9 remained associated with mitotic chromatin, facilitating transcriptional reactivation upon exiting mitosis. By dissecting the consequences of degrading SOX9 before mitosis, we found that its priming of dormancy-related CREs, combined with the recruitment of the Mediator kinase module, is instrumental for metastatic cells to enter quiescence and escape NK-mediated immune surveillance. These findings indicate that cancer dormancy is primed during mitosis by pro-metastatic TFs.

molecular biology↗

bioRxiv2024

Specific light-regime adaptations, terpenoid profiles and engineering potential in ecologically diverse Phaeodactylum tricornutum strains

Microalgae, and among them, the diatom Phaeodactylum tricornutum stand out with their remarkable versatility and metabolic engineering potential. Diatoms exhibit substantial variability in metabolism, photosynthetic physiology and environmental adaptation, even across the same species. These factors can affect the design and outcome of metabolic engineering strategies. In this study, we profiled the diversity of biotechnologically relevant traits of three P. tricornutum strains (Pt1, Pt6, and Pt9) under different light regimes to identify the most suitable chassis to be employed as bio-factory to produce high-value terpenoids. We conducted detailed assessments of these strains, using pulse amplitude modulated (PAM) fluorometry to measure photosynthetic efficiency and we analyzed the composition of pigments and triterpenoids, as main terpenoid metabolic sinks. Parameters such as the maximum quantum yield of PSII (Fv/Fm), the efficiency of excitation energy capture (Fv/Fm), and OJIP kinetics were used to estimate photosynthetic performance in different light regimes. Additionally, we evaluated their transformation efficiency and their capacity to produce heterologous monoterpenoids, using geraniol as a model product. Our findings revealed that Pt1, widely used in laboratories, exhibits robust growth and photosynthetic performance under standard laboratory conditions. Pt6, adapted to intertidal environments, shows unique resilience in fluctuating conditions, while Pt9, with its high-temperature tolerance, excels under continuous high irradiance. Additionally, this variability across strains and light conditions influenced the metabolic output of each strain. We concluded that understanding the physiological responses of different P. tricornutum strains to light is crucial for optimizing their use in metabolic engineering. The insights gained from this research will facilitate the strategic selection and exploitation of these strains in algae biotechnology, enhancing the production of commercially valuable compounds such as high-value terpenoids and derivatives. This comprehensive characterization of strains under varying light conditions offers a pathway to more efficient and targeted metabolic engineering applications. HighlightsO_LIPt1, Pt6, and Pt9 exhibit distinct physiology under different light regimes. C_LIO_LIPt9 is photosynthetically more performant in continuous light, Pt6 in photoperiod. C_LIO_LILight regimes affect pigments and triterpenoid content in all three strains. C_LIO_LIEach strain exhibits a specific carotenoid and triterpenoid composition. C_LIO_LIBacterial conjugation of episomes varies across strains, it is more efficient in Pt1. C_LIO_LIPt1 is suited for the heterologous synthesis of monoterpenes (geraniol). C_LI

plant biology↗

bioRxiv2024

Photoprotective mechanisms in Elysia species hosting Acetabularia chloroplasts shed light on host-donor compatibility in photosynthetic sea slugs

Sacoglossa sea slugs have garnered attention due to their ability to retain intracellular functional chloroplasts from algae, while degrading other algal cell components. While protective mechanisms that limit oxidative damage under excessive light are well documented in plants and algae, the photoprotective strategies employed by these photosynthetic sea slugs remain unresolved. Species within the genus Elysia are known to retain chloroplasts from various algal sources, but the extent to which the metabolic processes from the donor algae can be sustained by the sea slugs is unclear. By comparing their responses to high light conditions through kinetic analyses, molecular techniques, and biochemical assays, this study highlights significant differences between two photosynthetic Elysia species with chloroplasts derived from the green alga Acetabularia acetabulum. Notably, Elysia timida displayed remarkable tolerance to high light stress and sophisticated photoprotective mechanisms such as an active xanthophyll cycle, efficient D1 protein recycling, accumulation of heat-shock proteins and -tocopherol. In contrast, Elysia crispata exhibited absence or limitations in these photoprotective strategies. Our findings emphasize the intricate relationship between the host animal and the stolen chloroplasts, highlighting different capacities to protect the photosynthetic organelle from oxidative damage.

plant biology↗

bioRxiv2023

Boosting pro-vitamin A content and bioaccessibility in leaves by combining engineered biosynthesis and storage pathways with high-light treatments

The relevance of plants as food is expected to grow for a more sustainable diet. In this new context, improving the nutritional quality of plant-derived foods is a must. Biofortification of green leafy vegetables with pro-vitamin A carotenoids such as {beta}-carotene has remained challenging to date. Here we combined two strategies to achieve this goal. One of them (that we call strategy C) involves producing {beta}-carotene in extraplastidial locations of leaf cells to avoid the negative impacts on photosynthesis derived from changing the balance of carotenoids and chlorophylls in chloroplasts. The second approach (that we refer to as strategy P) involves the conversion of chloroplasts into non-photosynthetic, carotenoid-overaccumulating chromoplasts in some leaves, leaving other non-engineered leaves to sustain normal plant growth. Combination of these two strategies resulted in a 5- fold increase in the amount of {beta}-carotene in Nicotiana benthamiana leaves. Following several attempts to further improve {beta}-carotene leaf contents by metabolic engineering, hormone treatments and genetic screenings, it was found that promoting the proliferation of plastoglobules with high-light treatments not only improved {beta}-carotene accumulation but it also resulted in a much higher bioaccessibility. Combination of strategies C and P together with a high-light treatment increased the levels of accessible {beta}-carotene 30-fold compared to controls. We further demonstrate that stimulating plastoglobule proliferation with strategy P but also with high-light alone can also stimulate and hence improve {beta}-carotene contents and bioaccessibility in edible lettuce (Lactuca sativa) leaves, unveiling the power of non-GMO approaches for leaf biofortification.

plant biology↗

bioRxiv2022

Arabidopsis FIBRILLIN6 regulates carotenoid biosynthesis by directly promoting phytoene synthase activity

Carotenoids are health-promoting plastidial isoprenoids with essential functions in plants as photoprotectants and photosynthetic pigments in chloroplasts. They also accumulate in specialized plastids named chromoplasts, providing color to non-photosynthetic tissues such as flower petals and ripe fruit. Carotenoid accumulation in chromoplast requires specialized structures and proteins such as fibrillins. Although fibrillins were first reported as structural components of carotenoid sequestering structures in chromoplasts, later work revealed roles in chloroplasts and other plastid types. However, the association of fibrillins with carotenoids in plastids other than chromoplasts has remained unexplored. Here we show that a member of the fibrillin family, FBN6, interacts with phytoene synthase (PSY, the first committed and rate-determining step of the carotenoid pathway) to promote its enzymatic activity. Transient overexpression of FBN6 in Nicotiana benthamiana leaves results in a higher production of phytoene, the product of PSY activity, whereas loss of FBN6 activity in Arabidopsis thaliana mutants dramatically reduces the production of carotenoids during seedling deetiolation and after exposure to high light. Our work hence demonstrates that fibrillins not only promote the accumulation of carotenoids but also their biosynthesis.

plant biology↗

bioRxiv2022

Novel insights on the contribution of plastoglobules and reactive oxygen species to chromoplast differentiation

Enriching plant tissues in phytonutrients can be done by stimulating their biosynthesis but also by providing appropriate sink structures for their sequestering and storage. Chromoplasts are plastids specialized in the production and accumulation of carotenoids that are naturally formed in non-photosynthetic tissues such as flower petals and ripe fruit. Chromoplasts can also be artificially differentiated from leaf chloroplasts by boosting the production of phytoene (the first committed intermediate of the carotenoid pathway) with the bacterial phytoene synthase crtB. Here we show that crtB-induced leaf chromoplasts develop plastoglobules harboring high levels of carotenoids (mainly phytoene and pro-vitamin A {beta}-carotene) but also other nutritionally-relevant isoprenoids such as tocopherols (vitamin E) and phylloquinone (vitamin K1). Further promoting plastoglobule proliferation by exposure to intense (high) light resulted in a higher accumulation of these health-related metabolites but also an acceleration of the chloroplast-to-chromoplast conversion. We further show that production of reactive oxygen species (ROS) stimulates chromoplastogenesis. Our data suggest that, similar to that already described for decreased photosynthesis and enhanced carotenoid biosynthesis, ROS production is not just a consequence but a promoter of the chromoplast differentiation process.

plant biology↗

bioRxiv2020

Light quality signals generated by vegetation shade facilitate acclimation to reduced light quantity in shade-avoider plants

O_LIWhen growing in search for light, plants can experience continuous or occasional shading by other plants. Plant proximity causes a decrease in the ratio of red to far red light (low R:FR) due to the preferential absorbance of red light and reflection of far red light by photosynthetic tissues of neighboring plants. This signal is often perceived before actual shading causes a reduction in photosynthetically active radiation (low PAR). C_LIO_LIHere we investigated elongation, photosynthesis and photoacclimation responses in several Brassicaceae species to explore the possible connections between low R:FR and low PAR. C_LIO_LIA negative correlation was found in shade-tolerant Cardamine hirsuta and shade-avoider Arabidopsis thaliana seedlings (e.g., shade-tolerance was associated with a good adaptation to low PAR but a poor or null response to low R:FR exposure). However, they could be genetically uncoupled. Most interestingly, exposure to low R:FR of shade-avoider plants improved their photoacclimation to low PAR by triggering changes in photosynthesis-related gene expression, pigment accumulation and chloroplast ultrastructure. C_LIO_LIThese results indicate that low R:FR signaling unleashes molecular, metabolic and developmental responses that allow shade-avoider plants (including most crops) to adjust their photosynthetic capacity in anticipation of eventual shading by nearby plants. C_LI

plant biology↗

bioRxiv2020

Nested Stochastic Block Models Applied to the Analysis of Single Cell Data

Single cell profiling has been proven to be a powerful tool in molecular biology to understand the complex behaviours of heterogeneous system. The definition of the properties of single cells is the primary endpoint of such analysis, cells are typically clustered to underpin the common determinants that can be used to describe functional properties of the cell mixture under investigation. Several approaches have been proposed to identify cell clusters; while this is matter of active research, one popular approach is based on community detection in neighbourhood graphs by optimisation of modularity. In this paper we propose an alternative and principled solution to this problem, based on Stochastic Block Models. We show that such approach not only is suitable for identification of cell groups, it also provides a solid framework to perform other relevant tasks in single cell analysis, such as label transfer. To encourage the use of Stochastic Block Models, we developed a python library, schist, that is compatible with the popular scanpy framework.

bioinformatics↗

bioRxiv2020

From local resynchronization to global pattern recovery in the zebrafish segmentation clock

ABSTRACTRhythmic spatial gene expression patterns termed the segmentation clock regulate vertebrate body axis segmentation during embryogenesis. The integrity of these patterns requires local synchronization between neighboring cells by Delta-Notch signaling and its inhibition results in defective segment boundaries. The oscillating tissue deforms substantially throughout development, but whether such tissue-scale morphogenesis complements local synchronization during pattern generation and segment formation is not understood. Here, we investigate pattern recovery in the zebrafish segmentation clock by washing out a Notch inhibitor, allowing resynchronization at different developmental stages, and analyzing the recovery of normal segments. Although from previous work no defects are expected after recovery, we find that washing out at early stages causes a distinctive intermingling of normal and defective segments, suggesting unexpectedly large fluctuations of synchrony before complete recovery. To investigate this recovery behavior, we develop a new model of the segmentation clock combining key ingredients motivated by prior experimental observations: coupling between neighboring oscillators, a frequency profile, a gradient of cell mixing, tissue length change, and cell advection pattern. This model captures the experimental observation of intermingled normal and defective segments through the formation of persistent phase vortices of the genetic oscillators. Experimentally observed recovery patterns at different developmental stages are predicted by temporal changes of tissue-level properties, such as tissue length and cell advection pattern in the model. These results suggest that segmental pattern recovery occurs at two scales: local pattern formation and transport of these patterns through tissue morphogenesis, highlighting a generic mechanism of pattern dynamics within developing tissues.SIGNIFICANCE Interacting genetic oscillators can generate a coherent rhythm and a tissue-level pattern from an initially desynchronized state. Using experiment and theory we study resynchronization and pattern recovery of the zebrafish segmentation clock, which makes the embryonic body segments. Experimental perturbation of intercellular signaling with an inhibitor results in intermingled normal and defective segments. According to theory, this behavior may be caused by persistent local vortices scattered in the tissue during pattern recovery. Full pattern recovery follows dynamic global properties, such as tissue length and advection pattern, in contrast to other genetic oscillators in a static tissue such as circadian clocks. Our work highlights how dynamics of tissue level properties may couple to biochemical pattern formation in tissues and developing embryos.Competing Interest StatementThe authors have declared no competing interest.View Full Text

developmental biology↗

bioRxiv2019

A model of Zebrafish Avatar for co-clinical trials

Animal Avatars and co-clinical trials represent an emerging concept for implementing schemes of personalized medicine in oncology. In a co-clinical trial, the cancer cells of the patient tumor are xenotransplanted in the animal Avatar for drug efficacy studies and data collected in the animal trial are used to plan the best drug treatment in the patient trial. Recently, zebrafish has been proposed for implementing Avatar models but the lack of a general criterion for chemotherapy dose conversion from humans to fishes represents a limitation for conducting co-clinical trials.\n\nHere, we validate a simple, reliant and cost-effective Avatar model based on the use of zebrafish larvae; by crossing data from safety and efficacy studies, we found a basic formula for the estimation of the dose to be used for running co-clinical trials and we validate it in a clinical study enrolling 24 adult patients with solid cancers (XenoZ, NCT03668418).

cancer biology↗