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Results for “Cell Biology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 1,063 records · Page 59Linked to original sources

bioRxiv2023

Spontanously breaking of symmetry in overlapping cell instance segmentation using diffusion models

Instance segmentation is the task of assigning unique identifiers to individual objects in images. Solving this task requires breaking the inherent symmetry that semantically similar objects must result in distinct outputs. Deep learning algorithms bypass this break-of-symmetry by training specialized predictors or by utilizing intermediate label representations. However, many of these approaches break down when faced with overlapping labels that can appear, e.g., in biological cell layers. Here, we discuss the reason for this failure and offer a novel approach for instance segmentation based on diffusion models that breaks this symmetry spontaneously. Our method outputs pixel-level instance segmentations matching the performance of models such as cellpose on the cellpose fluorescent cell dataset while also permitting overlapping labels.

bioinformatics↗

bioRxiv2019

Cell-to-cell diversification in ERBB-RAS-MAPK signal transduction that produces cell-type specific growth factor responses

Growth factors regulate cell fates, including their proliferation, differentiation, survival, and death, according to the cell type. Even when the response to a specific growth factor is deterministic for collective cell behavior, significant levels of fluctuation are often observed between single cells. Statistical analyses of single-cell responses provide insights into the mechanism of cell fate decisions but very little is known about the distributions of the internal states of cells responding to growth factors. Using multi-color immunofluorescent staining, we have here detected the phosphorylation of seven elements in the early response of the ERBB-RAS-MAPK system to two growth factors. Among these seven elements, five were analyzed simultaneously in distinct combinations in the same single cells. Although principle component analysis suggested cell-type and input specific phosphorylation patterns, cell-to-cell fluctuation was large. Mutual information analysis suggested that cells use multitrack (bush-like) signal transduction pathways under conditions in which clear cell fate changes have been reported. The clustering of single-cell response patterns indicated that the fate change in a cell population correlates with the large entropy of the response, suggesting a bet-hedging strategy is used in decision making. A comparison of true and randomized datasets further indicated that this large variation is not produced by simple reaction noise, but is defined by the properties of the signal-processing network. Author SummaryHow extracellular signals, such as growth factors (GFs), induce fate changes in biological cells is still not fully understood. Some GFs induce cell proliferation and others induce differentiation by stimulating a common reaction network. Although the response to each GF is reproducible for a cell population, not all single cells respond similarly. The question that arises is whether a certain GF conducts all the responding cells in the same direction during a fate change, or if it initially stimulates a variety of behaviors among single cells, from which the cells that move in the appropriate direction are later selected. Our current statistical analysis of single-cell responses suggests that the latter process, which is called a bet-hedging mechanism is plausible. The complex pathways of signal transmission seem to be responsible for this bet-hedging.

systems biology↗

bioRxiv2022

A CRISPR-dCas13 RNA-editing tool to study alternative splicing

Alternative splicing allows multiple transcripts to be generated from the same gene to diversify the protein repertoire and gain new functions despite a limited coding genome. It can impact a wide spectrum of biological processes, including disease. However, its significance has long been underestimated due to limitations in dissecting the precise role of each splicing isoform in a physiological context. Furthermore, identifying key regulatory elements to correct deleterious splicing isoforms has proven equally challenging, increasing the difficulty to tackle the role of alternative splicing in cell biology. In this work, we take advantage of dCasRx, a catalytically inactive RNA targeting CRISPR-dCas13 ortholog, to efficiently switch alternative splicing patterns of endogenous transcripts without affecting overall gene expression levels in a cost-effective manner. Additionally, we demonstrate a new application for the dCasRx splice-editing system to identify key regulatory RNA elements of specific splicing events. With this approach, we are expanding the RNA toolkit to better understand the regulatory mechanisms underlying alternative splicing and its physiological impact in various biological processes, including pathological conditions.

molecular biology↗

bioRxiv2021

Glioblastoma remodeling of neural circuits in the human brain decreases survival

Gliomas synaptically integrate into neural circuits. Prior work has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth and gliomas increasing neuronal excitability. In this study we wanted to know how glioma induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. We use intracranial brain recordings during lexical retrieval language tasks in awake humans in addition to site specific tumor tissue biopsies and cell biology experiments. We find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumor-infiltrated cortex, beyond cortical excitation normally recruited in the healthy brain. Site-directed biopsies from functionally connected regions within the tumor are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumor cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumor regions compared to tumor regions with less functional connectivity. The degree of functional connectivity between glioblastoma and the normal brain negatively impacts both patient survival and language task performance. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumor proliferation and impairs cognition.

cancer biology↗

bioRxiv2024

Ccp1 depletion disrupts network integration of hippocampal parvalbumin interneurons

Post-translational modifications (PTMs) of microtubules (MTs) endow them with specific properties that are essential for key cellular functions, such as axonal transport. Polyglutamylation, a PTM that accumulates in long-lived MTs, has been linked to neurodegeneration in the cerebellum when in excess. While hyperglutamylation of MTs leads to neurodegeneration and disrupts the function of specific neuronal subtypes like Purkinje cells, cortical neurons, and hippocampal excitatory neurons, little is known about its impact on inhibitory interneurons and their functional integration into local networks. In this study, we generated a conditional knockout mouse model to deplete cytosolic carboxypeptidase 1 (Ccp1) in GABAergic neurons, a key MT deglutamylase expressed by hippocampal interneurons. Our findings reveal that the loss of Ccp1 has a profound effect on hippocampal parvalbumin (PV)-expressing interneurons, impairing their axonal transport and reducing their perisomatic inhibition of pyramidal cells (PCs) in the CA2 region of the hippocampus. Research TopicsMolecular Neuroscience, Cell Biology HighlightsO_LIDifferent subtypes of hippocampal interneurons express unique sets of (de)glutamylases and show varying levels of protein posttranslational glutamylation. C_LIO_LIParvalbumin interneurons become hyperglutamylated when Ccp1 activity is lost. C_LIO_LIThe loss of Ccp1 disrupts axonal transport in interneurons and is associated with decreased perisomatic inhibition of hippocampal pyramidal cells in the CA2 region. C_LI

neuroscience↗

bioRxiv2025

Systematic identification and characterization of regulators of aryl hydrocarbon receptor signaling

The human aryl hydrocarbon receptor (AHR) integrates chemical signals derived from the environment, gut microbes, and endogenous sources to regulate processes ranging from intestinal barrier integrity to xenobiotic detoxification. Despite strong evidence that dysregulation of AHR signaling is a causal factor in metabolic and autoimmune disorders, we currently lack a comprehensive understanding of the factors that regulate AHR activity in human cells. Here, we use genome-scale CRISPR screening to systematically identify regulators of AHR signaling in hepatocytes. The resulting datasets recapitulate the core AHR signaling pathway and identify a large network of regulators. Many of these factors have roles beyond AHR signaling, reflecting that AHR signaling is deeply integrated into human cell biology. We further dissect this network to reveal novel modes of regulation of AHR expression, protein levels, and signaling. For example, we find that the E3 ubiquitin ligase UBR5 sustains AHR signaling by counteracting degradation of ligand-bound AHR. Finally, we identify components of the AHR regulatory network that are specific to cell types and ligands as potential nodes to manipulate AHR signaling in a targeted manner for therapeutic benefit. Overall, our results define the regulatory network that underpins AHR activation, with implications for our understanding of host-microbe interactions and integrative chemosensation and the etiology of metabolic and inflammatory disorders.

genomics↗

bioRxiv2025

scConcept: Contrastive pretraining for technology-agnostic single-cell representations beyond reconstruction

Recent large-scale single-cell foundation models have shown promise for exploring cellular states, yet they often underperform compared to simpler, domain-specific methods, raising concerns about their broader applicability. A key limitation lies in their reliance on masked language modeling, which is well suited for generative language tasks but poorly aligned with learning rich cell-level embeddings required in single-cell biology. Moreover, the proliferation of transcriptomic technologies--from whole transcriptome dissociated assays to image-based targeted profiling--poses a major challenge for cross-platform generalization. Here, we align with recent advances in machine learning to move beyond reconstruction metrics, which often do not capture important sample variation. We present scConcept ("contrastive cell pre-training"), a transformer-based contrastive learning framework that directly optimizes cell embeddings by contrasting multiple views of cells. By replacing gene-level reconstruction with a cell-level identification task, scConcept learns robust representations that are invariant to count distributions and gene panel selection, across diverse assays and technologies. To highlight the capability of the proposed framework, we pretrain scConcept on a similar corpus of over 30 million single-cell RNA-seq profiles as recent foundation models. Our approach demonstrates superior performance not only compared to state-of-the-art pretrained foundation models but also domain-specific methods in various downstream tasks, including cell-type annotation, technology integration, dissociated to spatial cell-type transfer, spatial imputation, gene panel optimization, and mapping new technologies on already existing atlases. Our results highlight contrastive pretraining as a powerful alternative to reconstruction-based strategies for single-cell modeling, providing a path toward general-purpose, technology-agnostic cell representations.

bioinformatics↗

bioRxiv2018

Screening Mycobacterium tuberculosis secreted proteins identifies Mpt64 as eukaryotic membrane-binding virulence factor

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is one of the most successful human pathogens. One reason for its success is that Mtb can reside within host macrophages, a cell type that normally functions to phagocytose and destroy infectious bacteria. However, Mtb is able to evade macrophage defenses in order to survive for prolonged periods of time. Many intracellular pathogens secret virulence factors targeting host membranes and organelles to remodel their intracellular environmental niche. We hypothesized that Mtb exported proteins that target host membranes are vital for Mtb to adapt to and manipulate the host environment for survival. Thus, we characterized 200 exported proteins from Mtb for their ability to associate with eukaryotic membranes using a unique temperature sensitive yeast screen and to manipulate host trafficking pathways using a modified inducible secretion screen. We identified five Mtb exported proteins that both associated with eukaryotic membranes and altered the host secretory pathway. One of these secreted proteins, Mpt64, localized to the endoplasmic reticulum during Mtb infection of murine and human macrophages and was necessary for Mtb survival in primary human macrophages. These data highlight the importance of exported proteins in Mtb pathogenesis and provide a basis for further investigation into their molecular mechanisms.\n\nImportanceAdvances have been made to identify exported proteins of Mycobacterium tuberculosis during animal infections. These data, combined with transposon screens identifying genes important for M. tuberculosis virulence, have generated a vast resource of potential M. tuberculosis virulence proteins. However, the function of many of these proteins in M. tuberculosis pathogenesis remains elusive. We have integrated three cell biological screens to characterize nearly 200 M. tuberculosis exported proteins for eukaryotic membrane binding, host subcellular localization and interactions with host vesicular trafficking. In addition, we observed the localization of one exported protein, Mpt64, during M. tuberculosis infection of macrophages. Interestingly, although Mpt64 is exported by the Sec pathway, its delivery into host cells was dependent upon the action of the Type VII Secretion System. Finally, we observed that Mpt64 contributes to the virulence of M. tuberculosis during infection of primary human macrophages.

microbiology↗

bioRxiv2020

Cancer associated talin point mutations disorganise cell adhesion and migration

Talin-1 is a key component of the multiprotein adhesion complexes which mediate cell migration, adhesion and integrin signalling and has been linked to cancer in several studies. We analysed talin-1 mutations reported in the COSMIC (Catalogue of Somatic Mutations in Cancer) database and developed a bioinformatics pipeline to predict the severity of each mutation. These predictions were then assessed using biochemistry and cell biology experiments. With this approach we were able to identify several talin-1 mutations affecting integrin activity, actin recruitment and Deleted in Liver Cancer 1 localization. We explored potential changes in talin-1 signalling responses by assessing impact on migration, invasion and proliferation. Altogether, this study describes a pipeline approach of experiments for crude characterization of talin-1 mutants in order to evaluate their functional effects and potential pathogenicity. Our findings suggest that cancer related point mutations in talin-1 can affect cell behaviour and so may contribute to cancer progression.

cancer biology↗

bioRxiv2023

The substrate quality of CK2 target sites has a determinant role on their function and evolution

Most biological processes are regulated by peptide-recognition modules (PRMs) that bind to short linear motifs (SLiMs). Such interactions are rapidly reversible and often occur at low affinity. The protein kinase domain represents one such binding module, and known substrates may have full or only partial matches to the kinase recognition motif, a property known as substrate quality. However, it is not yet clear whether differences in substrate quality represent neutral variation along the phosphosite sequence or if these differences have functional consequences that are subject to selection. We explore this question in detail for the acidophilic kinase CK2. CK2 is well-characterised, clinically important, and a fundamental enzyme for many aspects of cell biology. We show that optimal CK2 sites are phosphorylated at maximal stoichiometries and found in many conditions whereas minimal substrates are phosphorylated at lower stoichiometries, are more dynamic during the cell cycle, and have regulatory functions. Optimal CK2 sites also tend to be older and more conserved than minimal sites, and evolutionary simulations indicate that the substrate quality of CK2 phosphosites is often tuned by selection. For intermediate target sites, increases or decreases to substrate quality may be deleterious, which we demonstrate experimentally for a CK2 substrate at the kinetochore. The results together suggest that minimal and optimal phosphosites are strongly differentiated in terms of their functional and evolutionary properties.

evolutionary biology↗

bioRxiv2016

Acidic pH is a Metabolic Switch for 2‐Hydroxyglutarate Generation and Signaling

2-hydroxyglutarate (2-HG) is an important epigenetic regulator, with potential roles in cancer and stem cell biology. The D (R) enantiomer (D-2-HG) is an oncometabolite generated from ketoglutarate (-KG) by mutant isocitrate dehydrogenase (ICDH), while L (S) 2-HG is generated by lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) in response to hypoxia. Since acidic pH is a common feature of hypoxia, as well as tumor and stem cell microenvironments, we hypothesized that pH may regulate cellular 2-HG levels. Herein we report that cytosolic acidification under normoxia moderately elevated 2-HG in cells, and boosting endogenous substrate -KG levels further stimulated this elevation. Studies with isolated LDH-1 and MDH-2 revealed that generation of 2-HG by both enzymes was stimulated several-fold at acidic pH, relative to normal physiologic pH. In addition, acidic pH was found to inhibit the activity of the mitochondrial L-2-HG removal enzyme L-2-HG dehydrogenase, and to stimulate the reverse reaction of ICDH (carboxylation of KG to isocitrate). Furthermore, since acidic pH is known to stabilize hypoxia-inducible factor (HIF), and 2-HG is a known inhibitor of HIF prolyl hydroxylases, we hypothesized that 2-HG may be required for acid-induced HIF stabilization. Accordingly, cells stably over-expressing L-2HGDH exhibited a blunted HIF response to acid. Together these results suggest that acidosis is an important and previously overlooked regulator of 2-HG accumulation and other oncometabolic events, with implications for HIF signaling.

Biochemistry↗

bioRxiv2023

FluoMALDI microscopy: matrix co-crystallization simultaneously enhances fluorescence and MALDI imaging

We report that co-crystallization of fluorophores with matrix-assisted laser desorption/ionization (MALDI) imaging matrices significantly enhances fluorophore brightness up to 79-fold, enabling the amplification of innate tissue autofluorescence. This discovery facilitates FluoMALDI, the imaging of the same biological sample by both fluorescence microscopy and MALDI imaging. Our approach combines the high spatial resolution and specific labeling capabilities of fluorescence microscopy with the inherently multiplexed, versatile imaging capabilities of MALDI imaging. This new paradigm eliminates the notion that MALDI matrices obscure and obstruct optical microscopy approaches, allowing to image the exact same cells in tissues, free of any physical changes between fluorescence and MALDI imaging, which minimizes data registration processes. Matrix-fluorophore co-crystallization also facilitates applications with insufficient fluorescence brightness. We showcase the capabilities of FluoMALDI imaging with endogenous and exogenous fluorophores and autofluorescence-based FluoMALDI of brain and kidney tissue sections. FluoMALDI will advance structural-functional microscopic imaging in cell biology, biomedicine, and pathology.

biochemistry↗

bioRxiv2016

MultiCellDS: a standard and a community for sharing multicellular data

Cell biology is increasingly focused on cellular heterogeneity and multicellular systems. To make the fullest use of experimental, clinical, and computational efforts, we need standardized data formats, community-curated \"public data libraries\", and tools to combine and analyze shared data. To address these needs, our multidisciplinary community created MultiCellDS (MultiCellular Data Standard): an extensible standard, a library of digital cell lines and tissue snapshots, and support software. With the help of experimentalists, clinicians, modelers, and data and library scientists, we can grow this seed into a community-owned ecosystem of shared data and tools, to the benefit of basic science, engineering, and human health.

systems biology↗

bioRxiv2021

Two timescales control the creation of large protein aggregates in cells

Protein aggregation is of particular interest due to its connection with many diseases and disorders. Many factors can alter the dynamics and result of this process, one of them being the diffusivity of the monomers and aggregates in the system. Here, we study experimentally and theoretically an aggregation process in cells, and we identify two distinct physical timescales that set the number and size of aggregates. The first timescale involves fast aggregation of small clusters freely diffusing in the cytoplasm, while, in the second one, the aggregates are larger than the pore size of the cytoplasm and thus barely diffuse, and the aggregation process is slowed down. However, the process is not entirely halted, potentially reflecting a myriad of active but random forces forces that stir the aggregates. Such slow timescale is essential to account for the experimental results of the aggregation process. These results could also have implications in other processes of spatial organization in cell biology, such as phase-separated droplets. O_TEXTBOXSIGNIFICANCEProtein aggregation is a physico-chemical process that underlies many diseases and disorders, such as Alzheimers or Huntingtons disease. Here, we study experimental and theoretically the effect of a sharp decrease of diffusivity in the aggregation dynamics, such as the one that could happen in the cell due to the presence of obstacles. We find that two different timescales are important in setting the size of large aggregates and we give an estimate of the size of the aggregate at which this dramatic change in behaviour occurs, which could not be exclusive of protein aggregation but affect many other intracellular processes. C_TEXTBOX

biophysics↗

bioRxiv2022

The microtubule-associated protein SlMAP70 interacts with SlIQD21 and regulates fruit shape formation in tomato

The shape of tomato fruits is closely correlated to microtubule organization and the activity of microtubule associated proteins (MAP), but insights into the mechanism from a cell biology perspective are still largely elusive. Analysis of tissue expression profiles of different microtubule regulators revealed that functionally distinct classes of MAPs are highly expressed during fruit development. Among these, several members of the plant-specific MAP70 family are preferably expressed at the initiation stage of fruit development. Transgenic tomato lines overexpressing SlMAP70 produced elongated fruits that show reduced cell circularity and microtubule anisotropy, while SlMAP70 loss-of-function mutant showed an opposite effect with flatter fruits. Microtubule anisotropy of fruit endodermis cells exhibited dramatic rearrangement during tomato fruit development, and SlMAP70-1 is likely implicated in cortical microtubule organization and fruit elongation throughout this stage by interacting with SUN10/SlIQD21a. The expression of SlMAP70 (or co-expression of SlMAP70 and SUN10/SlIQD21a) induces microtubule stabilization and prevents its dynamic rearrangement, both activities are essential for fruit shape establishment after anthesis. Together, our results identify SlMAP70 as a novel regulator of fruit elongation, and demonstrate that manipulating microtubule stability and organization at the early fruit developmental stage has a strong impact on fruit shape.

plant biology↗

bioRxiv2025

Multiple Xpa In vivo crystallization routes in HEK 293 human cells

Phase changes of macromolecules in living cells gained recently a major interest in cell biology as liquid liquid phase separation or liquid solid phase transition phenomenon being observed in increasing number of biological or pathological processes. Comprehensive characterization of these phases remains challenging and requires new methodological approaches for their complete description across spatial and temporal scales. We propose a combination of imaging methods applied to a model system and report the in vivo crystallization pathways of a macromolecule from its solution to crystalline states at the cell population level down to the meso scale. Combining various live fluorescence based techniques and a high resolution cryo imaging technique within unaltered cryopreserved cells, we could described the unexpectedly wide landscape of the in vivo crystalline states of the fluorescent coral derived protein xpa, gain information of crystal growth dynamics in cellulo, and provide hypothesis of the crystal nucleation requirements of this stochastic process.

biophysics↗

bioRxiv2025

Inverted Assembly of the Lens Within Ocular Organoids Reveals Alternate Paths to Ocular Morphogenesis

The eye is a complex organ composed of two main structures - the retina and the lens. It forms by the invagination of the lens forming head surface ectoderm embedding into the forming optic cup. This "outside-in" mode of morphogenesis ensures that the light focusing lens is positioned centrally inside of the eye in the highly constrained environment of the developing embryo. Advances in stem cell biology in the last decade introduced organoids as model to study organogenesis under normal and diseased conditions. However, even though strikingly similar at some points, it remained elusive to which extend the generation of individual structural features in organoids recapitulates in vivo organogenesis. Here we describe the generation of fish ocular organoids composed of both, lens and retina, using pluripotent embryonic cells from medaka (Oryzias latipes). Formation of the organoid lens followed the key molecular features of the process in vivo, including the establishment of lens progenitor cells and their subsequent differentiation into lens fiber cells. In a process dependent on the coordinated activity of BMP and FGF signaling, lens formation in ocular organoids was marked by the expression of key genes implicated in organismal lens development. Despite adhering to the basic molecular machinery of lens formation in vivo, the morphogenesis into a spherical lens followed an "inside-out" mode. Lens progenitor cells were initially established and differentiated into a spherical lens directly inside of the retina. Subsequent displacement of the lens from the center of the organoid towards its surface ultimately led to the formation of a cup-like shaped retina with a centrally positioned lens. Our study highlights that the self-organization of the organoid can favor routes that were not selected for in the developing embryo. Those routes can lead to an alternative, though highly similar outcome with the respect to achieving specific structural features in an unconstrained, embryo-free environment.

developmental biology↗

bioRxiv2022

Differential requirement for BRCA1-BARD1 E3 ubiquitin ligase activity in DNA damage repair and meiosis in the Caenorhabditis elegans germ line

The tumor suppressor BRCA1-BARD1 complex functions in many cellular processes; of critical importance to its tumor suppressor function is its role in genome integrity. Although RING E3 ubiquitin ligase activity is the only known enzymatic activity of the complex, the in vivo requirement for BRCA1-BARD1 E3 ubiquitin ligase activity has been controversial. Here we probe the role of BRCA1-BARD1 E3 ubiquitin ligase activity in vivo using C. elegans. Genetic, cell biological, and biochemical analyses of mutants defective for E3 ligase activity reveal both E3 ligase-dependent and independent functions of the complex in the context of DNA damage repair and meiosis. We show that E3 ligase activity is essential for BRCA1-BARD1 to concentrate at both DNA damage and recombination sites in meiotic germ cells, but not at DNA damage sites in proliferating germ cells. While BRCA1 alone is capable of monoubiquitylation, BARD1 is required with BRCA1 to promote polyubiquitylation. We find that the requirement for E3 ligase activity and BARD1 in DNA damage signaling and repair can be partially alleviated by driving the nuclear accumulation and self-association of BRCA1. Our data suggest that in addition to E3 ligase activity, BRC-1 serves a structural role for DNA damage signaling and repair while BRD-1 plays an accessory role to enhance BRC-1 function. Author SummaryBRCA1-BARD1 is a E3 ubiquitin ligase, which modifies proteins by the addition of the small protein ubiquitin. While mutations that disrupt E3 ligase activity and stability of the BRCA1-BARD1 complex lead to a predisposition for breast and ovarian cancer, the specific requirement for E3 ligase activity in tumor suppression is not known. Here we probe the function of E3 ligase activity and BARD1 in the maintenance of genome integrity by engineering point mutations that disrupt E3 ligase activity in C. elegans BRCA1 as well as a null mutation in BARD1. We find that while E3 ligase activity is important for genome integrity, the complex plays additional roles besides ubiquitylating proteins. Further, our data suggest that BRCA1 is the key functional unit of the complex while BARD1 is an accessory partner that enhances BRCA1s function. These findings may help explain why there is a higher prevalence of cancer-causing mutations in BRCA1 compared to BARD1.

genetics↗