Biology subjects

Levy, N.

Publications and source records attributed to Levy, N..

16 recordsLinked to original sources

bioRxiv2026

Coral Guard substrates accelerate growth and fragment fusion for coral restoration

Coral reefs are declining globally, creating an urgent need for scalable technologies that improve the efficiency and effectiveness of active reef restoration. Coral reef restoration is increasingly constrained by algal overgrowth, which suppresses coral growth, survival, and restoration efficiency. Building on the recently developed Coral Guard platform, we evaluate its restoration performance under long-term in situ coral nursery conditions and introduce Fusion Guard Tiles, a geometry-optimized Coral Guard design that accelerates microfragment fusion. We evaluated Coral Guard Plugs using the branching coral Stylophora pistillata under complementary ex situ conditions and Fusion Guard Tiles using the massive reef-building coral Porites evermanni in in situ coral nurseries. In P. evermanni, Fusion Guard Tiles increased lateral tissue growth 2.6-fold and three-dimensional tissue surface area growth by >2.7-fold after 6 months compared with conventional substrates. After 12 months, colony height and volume were approximately 4.0-fold and 2.2-fold greater, respectively, while complete fragment fusion occurred only on Fusion Guard Tiles. In S. pistillata, Coral Guard Plugs increased lateral tissue growth by [~]1.7-fold. Microcomputed tomography revealed 10-13% higher skeletal density in both species. In P. evermanni, Fusion Guard Tiles also increased symbiont density by 70% and tissue protein content by [~]2.5-fold relative to controls. Together, these findings demonstrate that Coral Guard substrates suppress algal competition while accelerating coral growth, skeletal development, and microfragment fusion, providing a scalable, low-maintenance technology to enhance coral nursery productivity and reef restoration.

bioengineering↗

bioRxiv2025

AMICI: Attention Mechanism Interpretation of Cell-cell Interactions

Spatial transcriptomic data enable study of cell-cell communication, yet current analysis tools often fail to provide dynamic, interpretable estimates of interactions and their spatial range across tissue. We present AMICI, an interpretable attention framework that jointly estimates interaction length scales, adaptively resolves sender-receiver subpopulations, and links communication to downstream gene programs. AMICI recovers ground-truth interactions in semi-synthetic data, uncovers gene programs linked to cell communication in the mouse cortex, and reveals length-scale-dependent tumor-immune signaling that reinforces estrogen receptor (ER) programs in breast cancer.

bioinformatics↗

bioRxiv2025

CytoVI: Deep generative modeling of antibody-based single cell technologies

Due to their robustness, dynamic range and scalability, antibody-based single cell technologies, such as flow cytometry, mass cytometry and CITE-seq, have become an irreplaceable part of routine clinics and a powerful tool for basic research. However, their analysis is complicated by measurement noise and bias, differences between batches, technology platforms, and restricted antibody panels. This results in a limited capacity to accumulate knowledge across technologies, studies, experimental batches, or across different antibody panels. Here, we present CytoVI - a probabilistic generative model designed to address these challenges and enable statistically rigorous and integrative analysis for antibody-based single cell technologies. We show that CytoVI outperforms existing computational methods and effectively handles a variety of integration scenarios. CytoVI enables key functionalities such as generating informative cell embeddings, imputing missing measurements, differential protein expression testing, and automated annotation of cells. We applied CytoVI to generate an integrated B cell maturation atlas across 350 proteins from a set of smaller antibody panels measured by conventional mass cytometry, and identified proteins associated with immunoglobulin class-switching in healthy humans. Using a cohort of B cell non-Hodgkin lymphoma patients measured by flow cytometry, CytoVI uncovered T cell states that are associated with disease. Finally, we show that CytoVI is a robust probabilistic framework for the analysis of standard diagnostic flow cytometry antibody panels, enabling the automated detection of tumor populations and diagnoses of incoming patient samples. CytoVI facilitates accurate and automated analysis in both preclinical and clinical settings and is available as open-source software at scvi-tools.org.

bioinformatics↗

bioRxiv2025

scVIVA: a probabilistic framework for representation of cells and their environments in spatial transcriptomics

Spatial transcriptomics provides a significant advance over studies of dissociated cells in that it reveals the environment in which cells reside, thus opening the way for a more complete description of their state and function. However, most current methods for embedding and discovery of cell states rely only on the cells own gene expression profile, thus raising the need for ways to account for the neighboring cells as well. Here, we introduce scVIVA, a deep generative model that leverages both cell-intrinsic and neighboring gene expression profiles to output stochastic embeddings of cell states as well as normalized gene expression profiles. We demonstrate that scVIVA produces informative fine-grained partitions of cells that reflect both their internal state and the surrounding tissue and that its generative model facilitates the testing of hypotheses of differential expression between tissue niches. We leverage these properties of scVIVA to uncover a spatially-restricted tumor-promoting endothelial population in breast cancer and niche-associated T cell states that are shared across multiple cancers. scVIVA is available as open source software within scvi-tools.org.

bioinformatics↗

bioRxiv2024

Bacteria-powered living materials enable coral larval settlement

The global decline of coral reefs calls for new strategies to rapidly restock coral populations and maintain ecosystem functions and services. Low recruitment success on degraded reefs hampers coral sexual propagation and contributes to limited genetic diversity and reef resilience. Here, we introduce a living bacteria-powered reef ink (Brink) for assisted coral recruitment. Brink can be rapidly applied to restoration substrates via photopolymerization, and it has been formulated to cultivate two settlement-inducing bacterial strains (Cellulophaga lytica and Thalassotalea euphylliae). Settlement assays performed with broadcast spawning (Montipora capitata) and brooding (Pocillopora acuta) Indo-Pacific corals showed that Brink-coated substrates increased settlement >5-fold compared to uncoated control substrates. Brink can be applied as a coating or 3D bioprinted, leading to various potential applications for integration with reef engineering. Our approach underscores the potential of using functional living materials for augmented ecosystem engineering and reef rehabilitation. SynopsisThis study introduces a functional and sustainable bacteria-powered living material that enhances coral settlement, promoting coral reef rehabilitation and ecosystem resilience.

bioengineering↗

bioRxiv2024

Novel hepatocyte-like liver organoids recapitulate crucial mature hepatic functions

Accurate liver disease modeling and drug toxicity testing still remain challenging as liver cells in vitro poorly resemble adult hepatocytes, as we previously demonstrated using whole transcriptome and cell identity analysis. To address this, we used our insights into hepatic modeling to develop hepatocyte-like liver organoids (HeLLOs), a novel human organoid model with mature hepatocyte functions superior to existing models. HeLLOs are easily established from (small) healthy or diseased liver tissues and rapidly expanded for an extended period in optimized culture conditions. Transcriptomic and functional analyses revealed that differentiated HeLLOs closely resemble fresh primary human hepatocytes (PHHs) and perform key hepatic functions such as gluconeogenesis, drug metabolism, and bile acid synthesis. We developed a HeLLO-based toxicity assay with higher sensitivity in predicting liver toxicity of known liver-toxic drugs compared to the gold-standard PHHs. By modeling disease-related mechanisms, such as bile acid transport, HeLLOs uncover transport-inhibition toxicity mechanisms of known liver toxic drugs. Single cell sequencing analysis of HeLLOs identified a heterogeneous cluster of cells with cholangiocyte-like and hepatocyte-like cells, overall resembling liver regenerative cells. As such, HeLLOs hold great promise for advancing liver disease modeling and drug testing. To our knowledge, HeLLOs are the best expandable liver model for predicting adverse drug reactions as well as modeling various liver disease mechanisms.

cell biology↗

bioRxiv2024

Mice lacking the nucleoporin NUP210L and BAF-paralogue BAF-L are infertile with disorganized manchette microtubules that invaginate the spermatid nucleus

During spermiogenesis, haploid round spermatids differentiate into spermatozoa. This involves nuclear elongation, chromatin compaction, cytoplasm reduction, and formation of the acrosome and the flagellum. These events are orchestrated by cytoskeletal elements - acroplaxome and manchette - that attach to the nuclear envelope (NE) except at the caudal pole where the nuclear pore complexes (NPCs) shift to form a dense array. Here, we use a genetic dissection approach to reveal function at the caudal NE, through the study of two spermatid-specific proteins, whose human orthologues persist there as spermatids elongate: NUP210L, a transmembrane nucleoporin and BAF-L, paralogue and interactor of chromatin protein BAF. In mice, inactivation of either BAF-L or NUP210L has no impact on fertility. However, we show here that in mice lacking NUP210L, two copies of BAF-L become essential for fertility; in Nup210l-/-,Banf2+/- or Nup210l-/-,Banf2-/- mice, most spermatids arrest during nuclear elongation (step 10-11) with mislocalized NPCs and disorganized manchette microtubules that frequently invaginate the nucleus from the caudal pole. Our results suggest that the NPC array, and BAF-L/BAF, ensure nuclear integrity at the caudal pole during spermatid remodeling. Summary: Nucleoporin NUP210L and BAF-paralogue BAF-L function redundantly during mouse spermatid nuclear remodeling to concentrate nuclear pores to the flagellar pole, organize the manchette cytoskeleton and prevent nuclear invagination by microtubules.

developmental biology↗

bioRxiv2024

A Tunable and Druggable Mechanism to Delay Forgetting of Olfactory Memories in C. elegans

The poet W.B Yeats wrote that "All that is personal soon rots, it must be packed in ice or salt". Here we show that in Caenorhabditis elegans nematodes, simple animals with just 302 neurons, memories are preserved on ice and in lithium salt. C. elegans nematodes can form associative memories, which are typically forgotten quickly. We discovered that when placed on ice, worms delay forgetting of specific olfactory memories by at least 8-fold. Delayed forgetting was canceled completely when the worms were gradually adapted to low temperatures, owing to a genetically-encoded program that turns acclimated worms cold-tolerant. RNA-seq, mutant analyses, and pharmacological assays revealed that regulation of membrane properties switches cold-induced delayed forgetting ON and OFF, and, remarkably, that lithium delays forgetting only in cold-sensitive but not cold-tolerant worms. We found that downregulation of the diacylglycerol pathway in the AWC sensory neurons is essential for lithium-mediated delayed forgetting, and using neuronal activity recordings located the memory trace to the downstream AIY interneurons. We suggest that the awesome genetic tractability of C. elegans might be harnessed to study the effects of lithium and cold temperatures on the brain, why it influences psychiatric disorders, and even more fundamentally how memory is stored and lost.

neuroscience↗

bioRxiv2023

E2F1 methylation by SETD6 regulates SETD6 expression via positive feedback mechanism

The protein lysine methyltransferase SETD6 has been shown to influence different cellular activities and are critically involved in the regulation of diverse developmental and pathological processes. However, the upstream signal which regulates the mRNA expression of SETD6 is not known. Bioinformatics analysis revealed that SETD6 promoter has a binding site for the transcription factor E2F1. Using various experimental systems, we confirmed that E2F1 binds to the SETD6 promoter and regulates SETD6 mRNA expression. Our further observation that this phenomenon is SETD6 dependent, suggested that SETD6 and E2F1 are linked. We next demonstrate that SETD6 mono-methylates E2F1 specifically at K117 in-vitro and in cells. Finally, we show that E2F1 methylation at K117 positively regulates the expression level of SETD6 mRNA. Depletion of SETD6 or overexpression of E2F1 K117R mutant which canot be methylated by SETD6, reverses the effect. Taken together, our data provide evidence for a positive feedback mechanism which regulates the expression of SETD6 by E2F1 in a SETD6 methylation dependent manner and highlight the importance of protein lysine methyltransferases and lysine methylation signaling in the regulation of gene transcription.

molecular biology↗

bioRxiv2020

Precision medicine for the rescue of specific impairments in social behavior associated with the A350V Iqsec2 mutation

In this study we tested the hypothesis that precision medicine guided therapy targeting glutamatergic neurotransmission could rescue behavioral deficits exhibited by mice carrying a specific mutation in the Iqsec2 gene. The IQSEC2 protein plays a key role in glutamatergic synapses and mutations in the IQSEC2 gene are a frequent cause of neurodevelopmental disorders. We have recently reported on the molecular pathophysiology of one such mutation A350V and demonstrated that this mutation downregulates AMPA type glutamatergic receptors (AMPAR) in A350V mice. Here we sought to identify behavioral deficits in A350V mice and hypothesized that we could rescue these deficits by PF-4778574, a positive AMPAR modulator. We found that A350V Iqsec2 mice exhibit specific deficits in sex preference and emotional state preference behaviors as well as in vocalizations when encountering a female mouse. The social discrimination deficits, but not the impaired vocalization, were rescued with PF-4778574. We conclude that social behavior deficits associated with the A350V Iqsec2 mutation may be rescued by enhancing AMPAR mediated synaptic transmission.

neuroscience↗

bioRxiv2020

Genetically flexible but conserved: a new essential motif in the C-ter domain of HIV-1 group M integrases

Using coevolution-network interference based on the comparison of two phylogenetically distantly related isolates, one from the main group M and the other from the minor group O of HIV-1, we identify, in the C-terminal domain (CTD) of integrase, a new functional motif constituted by four non-contiguous amino acids (N222K240N254K273). Mutating the lysines abolishes integration through decreased 3-processing and inefficient nuclear import of reverse transcribed genomes. Solution of the crystal structures of wt and mutated CTDs shows that the motif generates a positive surface potential that is important for integration. The number of charges in the motif appears more crucial than their position within the motif. Indeed, the positions of the K could be permutated or additional K could be inserted in the motif, generally without affecting integration per se. Despite this potential genetic flexibility, the NKNK arrangement is strictly conserved in natural sequences, indicative of an effective purifying selection exerted at steps other than integration. Accordingly, reverse transcription was reduced even in the mutants that retained wt integration levels, indicating that specifically the wt sequence is optimal for carrying out the multiple functions integrase exerts. We propose that the existence of several amino acids arrangements within the motif, with comparable efficiencies of integration per se, might have constituted an asset for the acquisition of additional functions during viral evolution. IMPORTANCEIntensive studies on HIV-1 have revealed its extraordinary ability to adapt to environmental and immunological challenges, an ability that is also at the basis of antiviral treatments escape. Here, by deconvoluting the different roles of the viral integrase in the various steps of the infectious cycle, we report how the existence of alternative equally efficient structural arrangements for carrying out one function opens on the possibility of adapting to the optimisation of further functionalities exerted by the same protein. Such property provides an asset to increase the efficiency of the infectious process. On the other hand, though, the identification of this new motif provides a potential target for interfering simultaneously with multiple functions of the protein.

molecular biology↗

bioRxiv2020

Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay

Improving the accuracy of variant interpretation during diagnostic sequencing is a major goal for genomic medicine. In order to explore an often overlooked splicing effect of missense variants, we developed the functional assay ("minigene") for the majority of exons of CAPN3, the gene responsible for Limb Girdle Muscular Dystrophy (LGMD). By systematically screening 21 missense variants distributed along the gene, we found that eight clinically relevant missense variants located at a certain distance from the exon/intron borders (deep exonic missense variants) disrupted normal splicing of CAPN3 exons. Several recent machine learning based computational tools failed to predict splicing impact for the majority of these deep exonic missense variants, highlighting the importance of including variants of this type in the training sets during the future algorithm development. Overall, 24 variants in CAPN3 gene were explored, leading to the change in the ACMG classification of seven of them when results of the "minigene" functional assay were taken into account. Our findings reveal previously unknown splicing impact of several clinically important variants in CAPN3 and draw attention to the existence of deep exonic variants with a disruptive effect on gene splicing that could be overlooked by the current approaches in clinical genetics.

genetics↗

bioRxiv2018

Prediction of Mutations to Control Pathways Enabling Tumour Cell Invasion with the CoLoMoTo Interactive Notebook (Tutorial)

Boolean and multi-valued logical formalisms are increasingly used to model complex cellular networks. To ease the development and analysis of logical models, a series of software tools have been proposed, often with specific assets. However, combining these tools typically implies a series of cumbersome software installation and model conversion steps. In this respect, the CoLoMoTo Interactive Notebook provides a joint distribution of several logical modelling software tools, along with an interactive web Python interface easing the chaining of complementary analyses. In this protocol, we demonstrate the assets of this approach through the analysis of a computational model of biological network. Our computational workflow combines (1) the importation of a GINsim model and its display, (2) its format conversion using the Java library BioLQM, (3) the formal prediction of mutations using the OCaml software Pint, (4) the model checking using the C++ software NuSMV, (5) quantitative stochastic simulations using the C++ software MaBoSS, and (6) the visualisation of results using the Python library matplotlib. Starting with a recent Boolean model of the signalling network controlling tumour cell invasion and migration, our model analysis culminates with the prediction of sets of mutations presumably involved in a metastatic phenotype.

systems biology↗

bioRxiv2018

The CoLoMoTo Interactive Notebook: Accessible and Reproducible Computational Analyses for Qualitative Biological Networks

Analysing models of biological networks typically relies on workflows in which different software tools with sensitive parameters are chained together, many times with additional manual steps. The accessibility and reproducibility of such workflows is challenging, as publications often overlook analysis details, and because some of these tools may be difficult to install, and/or have a steep learning curve. The CoLoMoTo Interactive Notebook provides a unified environment to edit, execute, share, and reproduce analyses of qualitative models of biological networks. This framework combines the power of different technologies to ensure repeatability and to reduce users learning curve of these technologies. The framework is distributed as a Docker image with the tools ready to be run without any installation step besides Docker, and is available on Linux, macOS, and Microsoft Windows. The embedded computational workflows are edited with a Jupyter web interface, enabling the inclusion of textual annotations, along with the explicit code to execute, as well as the visualisation of the results. The resulting notebook files can then be shared and re-executed in the same environment. To date, the CoLoMoTo Interactive Notebook provides access to software tools including GINsim, BioLQM, Pint, MaBoSS, and Cell Collective for the modelling and analysis of Boolean and multi-valued networks. More tools will be included in the future. We developed a Python interface for each of these tools to offer a seamless integration in the Jupyter web interface and ease the chaining of complementary analyses.

bioinformatics↗

bioRxiv2017

Osteo-Oto-Hepato-Enteric Syndrome (O2HE) is caused by loss of function mutations in UNC45A

Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with hitherto unknown syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing and bone fragility, a clinical entity we have termed O2HE (Osteo-Oto-Hepato-enteric) syndrome. Whole exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A), as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss of function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.

genetics↗

bioRxiv2017

Random Walk With Restart On Multiplex And Heterogeneous Biological Networks

Recent years have witnessed an exponential growth in the number of identified interactions between biological molecules. These interactions are usually represented as large and complex networks, calling for the development of appropriated tools to exploit the functional information they contain. Random walk with restart is the state-of-the-art guilt-by-association approach. It explores the network vicinity of gene/protein seeds to study their functions, based on the premise that nodes related to similar functions tend to lie close to each others in the networks.\n\nIn the present study, we extended the random walk with restart algorithm to multiplex and heterogeneous networks. The walk can now explore different layers of physical and functional interactions between genes and proteins, such as protein-protein interactions and co-expression associations. In addition, the walk can also jump to a network containing different sets of edges and nodes, such as phenotype similarities between diseases.\n\nWe devised a leave-one-out cross-validation strategy to evaluate the algorithms abilities to predict disease-associated genes. We demonstrate the increased performances of the multiplex-heterogeneous random walk with restart as compared to several random walks on monoplex or heterogeneous networks. Overall, our framework is able to leverage the different interaction sources to outperform current approaches.\n\nFinally, we applied the algorithm to predict genes candidate for being involved in the Wiedemann-Rautenstrauch syndrome, and to explore the network vicinity of the SHORT syndrome.\n\nThe source code and the software are freely available at: https://github.com/alberto-valdeolivas/RWR-MH.

systems biology↗