Biology subjects

Cohen, E.

Publications and source records attributed to Cohen, E..

At least 19 recordsLinked to original sources

bioRxiv2026

Sex- and age-dependent control of dopamine function by LRRK2, and rapid reversal of dopamine release deficits in the LRRK2-G2019S knock-in mouse model of Parkinson's Disease.

No disease-modifying therapy exists for Parkinson's disease (PD). At diagnosis (~65y), ~70% of nigrostriatal dopamine (DA) axons may have degenerated, so identifying when and how striatal axon function declines is critical. LRRK2 hyperactivity is observed in LRRK2 and VPS35 familial cases, and also idiopathic PD. Thus suggests LRRK2 hyperfunction is a common pathophysiological feature of PD. LRRK2 inhibitors are currently in human trials, yet their effects on brain circuit function are poorly characterized. By optical imaging of iGluSnFR and dLight we measured striatal glutamate and DA release in WT, LRRK2 G2019S (LKI) and VPS35 D620N (VKI) knock-in mice, across adult ages and sexes, with and without LRRK2 inhibition. In WT mice, ongoing LRRK2 activity regulated DA release in an age- and sex-dependent manner. Acute inhibition reversed basal sex differences in striatal glutamate and DA release in aged mice, and potentiated DA release more in middle-aged females than males. In LKI mice, DA release declined progressively, first in males, then females, after maturation to full adulthood, and remained impaired in very old LKI and VKI mice. Release deficits in aged LKI and VKI mice were resistant to acute LRRK2 inhibition, but 2h inhibition rapidly reversed deficits in middle-aged LKI males and females. We conclude that LRRK2 activity, and inhibition effects, depend on age, sex, and genotype, with direct implications for the design and timing of current LRRK2 inhibitor clinical trials for PD.

neuroscience↗

bioRxiv2026

Physiological Group Synchrony Captures Individual Perceptions of Trust and Cohesion and Collective Performance through Multi-Channel Network Analysis

Humans coordinate in groups, yet much of what we know about coordination comes from dyadic interaction. In groups, however, how much people synchronize may not be enough. Pairwise synchrony can be distributed across teammates: who synchronizes with whom, and how these connections are distributed, may carry distinct social information. Here, we tested whether physiological group synchrony can be understood as a network topology of interpersonal coordination rather than as an aggregate of dyadic alignments. A total of 33 groups (N = 161 participants) completed cooperative and competitive joint drumming tasks while cardiac inter-beat intervals (IBI) and electrodermal activity (EDA) were recorded simultaneously. Pairwise physiological synchrony was estimated using lagged cross-correlation and used to construct synchrony-based networks. IBI-based networks showed stronger and broader cardiac connectivity during cooperation, with cardiac coupling also increasing during competitive drumming relative to baseline. EDA-based networks also showed task-sensitive changes in node-level connectivity and captured social and behavioral dimensions of group interaction, linking trust and cohesion to node-level connectivity, and collective behavioral synchrony to lower clustering and higher local efficiency. Together, these findings show that the social meaning of physiological group synchrony lies not only in how much individuals align, but in how physiological alignment is distributed across people, relationships, and biological systems. By preserving this configuration, synchrony-based network analysis captures information about group experience that is lost when synchrony is reduced to an average dyadic score, providing a route toward understanding group synchrony as a flexible, selective, and distributed property of social coordination.

physiology↗

bioRxiv2025

Tissue-level division of labor is coordinated across organs through universal programs and context-specific adaptations

Fibroblasts, macrophages, and endothelial cells are common to most mammalian tissues, where they support homeostasis, repair, and immune regulation. Yet how they coordinate their functions across diverse tissue environments remains unclear. Here, we analyze single-cell RNA sequencing data from 14 human tissues using Pareto optimality framework and identify 16 archetypes - specialized transcriptional programs representing functional tradeoffs. These include universal archetypes shared across tissues and tissue-specific archetypes shaped by local context. We find that tissues align along a continuous axis of archetype distributions, from metabolically active to barrier organs, reflecting coordinated functional adaptation. Using ligand-receptor enrichment mapping, we reveal task-specific crosstalk across cell types, suggesting that intercellular communication underlies supportive division of labor. Applying this analysis to mouse tissues, we find similar patterns, indicating evolutionary conserved tradeoffs. These findings provide a framework for understanding how division of labor is coordinated in health and how its dysregulation may contribute to disease.

systems biology↗

bioRxiv2025

Novel Predictive Spatial Biomarker in Non-Small Cell Lung Carcinoma: The Diversity of Niches Unlocking Treatment Sensitivity (DONUTS)

Probabilistic spatial modelling techniques developed on large-scale tumor-immune Atlases ([~]35M individually mapped cells; 50,000 high power fields) were used to characterize predictive features of treatment-responsive lung cancer. We identified CD8+FoxP3+ cell density as a robust pre-treatment biomarker for outcomes across disease stages and therapy types. In parallel, single-cell RNAseq studies of CD8+FoxP3+ T-cells revealed an activated, early effector phenotype, substantiating an anti-tumor role, and contrasting with CD4+FoxP3+ T-regulatory cells. A spatial biomarker was developed using an empirical probabilistic model to define the immediate cell neighbors or niche surrounding CD8+FoxP3+ cells and proximity to the tumor-stromal boundary. The resultant Diversity of Niches Unlocking Treatment Sensitivity (DONUTS) are more prevalent than the CD8+FoxP3+ cells themselves, mitigating sampling error in small biopsies. Further, the DONUTS only require four markers, are additive to PD-L1, and associate with tertiary lymphoid structure counts. Taken together, the DONUTS represent a next-generation predictive biomarker poised for clinical implementation. HIGHLIGHTSO_LILarge-scale tumor-immune Atlases drive robust computational biomarker development C_LIO_LICD8+FoxP3+ cells are anti-tumor T-cells and predict response to therapy C_LIO_LIThe niches or spatial donuts around CD8+FoxP3+ cells boost biomarker performance C_LIO_LICD8+FoxP3+ donuts are hallmarks of a larger immune organization that includes TLS C_LI

pathology↗

bioRxiv2025

Large Scale Cell Painting Guided Compound Selection Reveals Activity Cliffs and Functional Relationships

Traditional structure-based pre-screen compound selection relies on the assumption that chemical similarity implies similar biological activity. This paradigm narrows the exploration of chemical space and often fails to account for functional convergence, where structurally diverse compounds act through distinct targets to produce similar phenotypic effects. As a result, compounds with therapeutic potential may be overlooked. To overcome this constraint, we introduce a training-free, transfer learning-based method for large scale compound preselection that leverages deep phenotypic profiling of human cells. Notably, this enables robust pairwise comparison of phenotypic signatures across any source of the entire JUMP-CP, the largest publicly available cell painting dataset (112,480 compounds), preserving biological signals while mitigating batch effects. Validated across 65 high-throughput assays--including in vitro and in cellulo systems--our method provides efficient pre-screen enrichment of biologically active compounds, bypassing the blind spots of structure-centric approaches. Interestingly, because it is large scale, it also allows for a comprehensive analysis of structure-phenotypic activity relationships, revealing potentially thousands of compound activity cliffs, where minimal chemical changes in structure may result in profound phenotypic shifts. We show that these cliffs capture subtle, atom-level determinants of bioactivity that cannot be accessed by structure-based models. Furthermore, we demonstrate that structurally diverse compounds targeting different genes in the same biological pathway can induce either convergent or opposite phenotypes--a phenomenon validated across 30 pathways, hundreds of genes, and thousands of compounds. Finally, to support the broader community, we propose Phenoseeker, a web-based tool enabling instant retrieval of JUMP-CP compounds with similar phenotypic profiles. Together, these findings position phenotypic profiling not merely as a complementary tool, but as a transformative and scalable framework for navigating chemical space through a biological lens. By capturing rich morphological signatures that reflect functional outcomes--regardless of structural similarity--this approach enables the discovery of bioactive compounds, novel mechanisms of action, and unexpected target-pathway relationships. Applied at the scale of the JUMP-CP dataset, phenotypic profiling emerges as a powerful strategy for prioritizing compounds, illuminating activity cliffs, and accelerating the identification of therapeutically relevant candidates across diverse biological contexts.

bioinformatics↗

bioRxiv2025

The spontaneous neoantigen-specific CD4+ T cell response to a growing tumor is functionally and phenotypically diverse.

CD4+ T cells play critical roles in the positive and negative regulation of cellular immunity through the many functional subsets they comprise. The progressive growth of immunogenic tumors which nonetheless generate mutation-specific T cells suggests that effective immune control may be avoided or suppressed at the level of the neoantigen-specific CD4+ T cell response. We used a tetramer specific for a validated neoantigen, CTLCH129>Q/I-Ek, to characterize the ontogeny of natural CD4+ T cell responses to an aggressive and poorly immunogenic Major Histocompatibility Complex Class II (MHCII)-deficient tumor, SCC VII, during progressive growth or following therapeutic peptide vaccination. We find that the natural CD4+ T cell response to a growing tumor is phenotypically and functionally diverse, with distinct subsets including type 1 helper (Th1), T follicular helper (Tfh)-like, and regulatory T cell (Treg) lineages appearing as early as 9 days after tumor implantation. Therapeutic vaccination using the CLTCH129>Q peptide in adjuvant plus -PD-1 sharply reduces the frequency of CLTCH129>Q-specific Treg frequency in both tumor and tumor-draining lymph node (tdLN). Single cell transcriptomic analysis of CLTC-specific CD4+ T cells recapitulated and extended the diversity of the response, with TCRs of varying affinity found within each functional subset. The TCR affinity differences did not strictly correlate with function, however, as even the lowest affinity TCRs isolated from Treg can mediate therapeutic efficacy against established tumors in the setting of adoptive cellular therapy (ACT). These findings offer unprecedented insight into the functional diversity of a natural neoantigen-specific CD4+ T cell response and show how immunotherapeutic intervention influences the phenotype, magnitude, and efficacy of the anti-tumor immune response. What is already known on this topicLittle is known about the ontogeny, architecture, development of the CD4+ NeoAg-specific repertoire induced by progressively-growing tumor. This study was performed to address this topic and contribute new information to aid in its understanding What this study addsThis study reveals that the NeoAg-specific CD4+ T cell response to a growing tumor is phenotypically and functionally diverse, featuring a range of functional T cells subsets including TH1, TFH, and Treg expressing a range of functional TCR avidities, and demonstrates how an immunotherapeutic NeoAg vaccine can alter their relative composition within the tumor and tumor-draining lymph node. How this study might affect research, practice or policyThis study offers new insights into the diversity of NeoAg-specific CD4+ T cells and their response to a tumor in the presence or absence of immunotherapeutic intervention. This information could lead to new approaches to immune monitoring in the clinical setting of checkpoint blockade immunotherapy and cancer vaccines. Furthermore, we show that Treg can be a potent source of TCRs that can mediate therapeutic benefit in the setting of adoptive cell therapy (ACT).

immunology↗

bioRxiv2025

Keratin 15 promotes a progenitor cell statein basal keratinocytes of skin epidermis

The type I intermediate filament proteins keratin 14 (K14) and keratin 15 (K15) are common to all complex epithelia. K14 is highly expressed by progenitor keratinocytes, in which it provides essential mechanical integrity and gates keratinocyte entry into differentiation by sequestering YAP1, a transcriptional effector of Hippo signaling, to the cytoplasm. K15 has long been used as a marker of hair bulge stem cells, though its specific role in skin epithelia is unknown. Here we show that the lack of two biochemical determinants, a cysteine residue within the stutter motif of the central rod domain and a 14-3-3 binding site in the N-terminal head domain, renders K15 unable to effectively sequester YAP1 in the cytoplasm like K14 does. We combine insight obtained from cell culture and transgenic mouse models with computational analyses of transcriptomics data and propose a model in which a higher K15:K14 ratio promotes a progenitor state and antagonizes differentiation in keratinocytes of the epidermis. SUMMARYThe type I intermediate filament keratin 15 (K15) exhibits preferential expression in a subset of skin keratinocytes with stem-like properties. We report that K15 promotes the progenitor state by counteracting the ability of the related K14 to negatively regulate YAP1, a terminal effector of Hippo signaling.

developmental biology↗

bioRxiv2024

Keratin 16 spatially inhibits type I interferon responses in stressed skin

The stress-induced keratin 16 is broadly used as a biomarker in inflammatory skin disorders while pathogenic variants in KRT16 cause pachyonychia congenita (PC), a condition in which differentiation and homeostasis are disrupted in palmoplantar epidermis and epithelial appendages. How K16 impacts these disorders at a molecular level is poorly understood. Here we report that K16 spatially restricts type I interferon (IFN) signaling and innate immunity in palmoplantar keratoderma (PPK) lesions in PC patients, imiquimod- and phorbol ester-induced models of sterile inflammation in mouse skin, and poly(I:C)-treated human keratinocytes ex vivo. Mechanistically, K16 interacts with effectors of the RIG-I-like receptor (RLR) pathway, including 14-3-3{varepsilon}, and inhibits the 14-3-3{varepsilon}:RIG-I interaction upstream of IFN activation. Topical application of the JAK inhibitor Ruxolitinib reduces the severity of PC-PPK-like lesions in Krt16 null mice. These findings uncover a new paradigm for keratin-dependent regulation of innate immunity and suggest a new approach to PC treatment. One sentence summaryKRT16 negatively regulates type I interferon signaling and innate immune responses in the skin, offering insight into the pathophysiology of inflammatory skin diseases including pachyonychia congenita, psoriasis and others.

immunology↗

bioRxiv2024

TGFβ1-TNFα regulated secretion of neutrophil chemokines is independent of epithelial-mesenchymal transitions in breast tumor cells

Neutrophils have tumor-promoting roles in breast cancer and are detected in higher numbers in aggressive breast tumors. How aggressive breast tumors recruit neutrophils remains undefined. Here, we investigated the roles of TGF-{beta}1 and TNF- in the regulation of neutrophil recruitment by breast cancer cells. TGF-{beta}1 and TNF- are pro-inflammatory factors upregulated in breast tumors and induce epithelial to mesenchymal transitions (EMT), a process linked to cancer cell aggressiveness. We report that, as expected, dual treatment with TGF-{beta}1 and TNF- induces EMT signatures in premalignant M2 cells, which are part of the MCF10A breast cancer progression model. Conditioned media (CM) harvested from M2 cells treated with TGF-{beta}1/TNF- gives rise to amplified neutrophil chemotaxis compared to CM from control M2 cells. This response correlates with higher levels of the neutrophil chemokines CXCL1, CXCL2, and CXCL8 and is significantly attenuated in the presence of a CXCL8-neutralizing antibody. Furthermore, we found that secretion of CXCL1 and CXCL8 from treated M2 cells depends on p38MAPK activity. By combining gene editing, immunological and biochemical approaches, we show that the regulation of neutrophil recruitment and EMT signatures are not mechanistically linked in treated M2 cells. Finally, analysis of publicly available cancer cell line transcriptomic databases revealed a significant correlation between CXCL8 and TGF-{beta}1/TNF--regulated or effector genes in breast cancer. Together, our findings establish a novel role for the TGF-{beta}1/TNF-/p38 MAPK signaling axis in regulating neutrophil recruitment in breast cancer, independent of TGF-{beta}1/TNF- regulated EMT.

cancer biology↗

bioRxiv2024

The ontogeny of chimpanzee technological efficiency

Primate extractive foraging requires years of dedicated learning. Throughout this period, learners peer at conspecifics engaging in the behaviour ("models"), interacting with the model and their tools, and sometimes stealing the freshly extracted resource. This also corresponds to an extended period of tolerance from the models. Yet the long-term effect of variation in experiences during this period on the technological efficiency of individuals is unknown for primate tool use, and no research has assessed the role of both the learner and the model(s) in generating individual differences. Using >680 hours of video spanning 25 years, we assessed whether experiences during the stone tool use social learning period ("early learning period"; ages 0-5) predicted the post-early learning period (ages 6+) technological efficiency in wild chimpanzees in Bossou, Guinea. We found that learners varied in how frequently they peered at the models whole nut-cracking bouts, how many learning opportunities their mothers presented, and the amount of tolerance and intolerance they experienced from all selected models. Learners who experienced more intolerance became less efficient tool users, whereas learners who were exposed to more social learning opportunities and tolerance became more efficient. Peering at the whole nut-cracking bout decreased subsequent efficiency, hinting at learners acquiring less efficient cultural components of the behaviour. Our findings highlight the role of social learning in the acquisition of stone tool use and support the view that social learning opportunities within a tolerant environment are key in explaining the emergence and maintenance of complex forms of primate technology. Significance StatementThe capacity and inclination to learn from others, along with social learning opportunities provided by tolerant groupmates, are thought to have enabled the evolution of technology in primates, including hominins. The influence of the learning period on long-term individual variation in technological efficiency remains unknown for non-human primates but has significant implications for cultural transmission and evolution. We provide longitudinal support for the hypothesis that exposure to social learning opportunities during development predicts subsequent technological efficiency. Moreover, we show that low amounts of intolerance, not just general tolerance, is key in the ontogeny of technological efficiency. Finally, we find aspects of behavioural acquisition relating to accurate transmission of cultural traits rather than to learning to use tools efficiently.

animal behavior and cognition↗

bioRxiv2024

Pesticide chemical leads inhibiting protein-protein interactions

Pesticides, especially herbicides, have revolutionized agriculture by providing energy-efficient solutions for pest control that replaces labor-intensive cultivation methods. However, the widespread evolution of pesticide resistance poses a significant challenge to current agriculture. Most pesticides function by binding to specific pockets on target enzymes, enabling a single mutation to confer resistance. An alternative approach is the disruption of protein-protein interactions (PPI), thus for resistance to occur, it requires complementary mutations on both interacting partners. Despite extensive efforts, no herbicides with new modes of action have been commercialized for decades. Thus, we focused on the discovery and design of small molecule inhibitors that target the interface of the PPI complex of O-acetylserine sulfhydrylase (OASS) and serine acetyltransferase (SAT), key plant enzymes involved in the biosynthesis of the essential amino acid cysteine. Using in silico filtering techniques on a virtual library of 30 million small molecules, we identified initial hits capable of binding OASS and interfering with its interaction with a peptide derived from SAT. Subsequently, we conducted chemical optimizations to evaluate biophysical enzyme disruption, followed by cellular and in-planta activity in plants. These new compounds described herein can serve as promising starting points for further optimization as herbicides acting on a new mode of action.

biochemistry↗

bioRxiv2023

Conserved and derived expression patterns and positive selection on dental genes reveal complex evolutionary context of ever-growing rodent molars

Continuously growing teeth are an important innovation in mammalian evolution, yet genetic regulation of continuous growth by stem cells remains incompletely understood. Dental stem cells responsible for tooth crown growth are lost at the onset of tooth root formation. Genetic signaling that initiates this loss is difficult to study with the ever-growing incisor and rooted molars of mice, the most common mammalian dental model species, because signals for root formation overlap with signals that pattern tooth size and shape (i.e., cusp patterns). Different species of voles (Cricetidae, Rodentia, Glires) have evolved rooted and unrooted molars that have similar size and shape, providing alternative models for studying roots. We assembled a de novo genome of Myodes glareolus, a vole with high-crowned, rooted molars, and performed genomic and transcriptomic analyses in a broad phylogenetic context of Glires (rodents and lagomorphs) to assess differential selection and evolution in tooth forming genes. We identified 15 dental genes with changing synteny relationships and six dental genes undergoing positive selection across Glires, two of which were undergoing positive selection in species with unrooted molars, Dspp and Aqp1. Decreased expression of both genes in prairie voles with unrooted molars compared to bank voles supports the presence of positive selection and may underlie differences in root formation. Bulk transcriptomics analyses of embryonic molar development in bank voles also demonstrated conserved patterns of dental gene expression compared to mice, with species-specific variation likely related to developmental timing and morphological differences between mouse and vole molars. Our results support ongoing evolution of dental genes across Glires, revealing the complex evolutionary background of convergent evolution for ever-growing molars.

evolutionary biology↗

bioRxiv2023

The germline regulates longevity and somatic repair in a sex-specific manner

Classical evolutionary theories propose tradeoffs between reproduction, damage repair, and lifespan. However, the specific role of the germline in shaping vertebrate aging remains largely unknown. Here, we use the turquoise killifish (N. furzeri) to genetically arrest germline development at discrete stages, and examine how different modes of infertility impact life-history. We first construct a comprehensive single-cell gonadal atlas, providing cell-type-specific markers for downstream phenotypic analysis. Next, we show that germline depletion - but not arresting germline differentiation - enhances damage repair in female killifish. Conversely, germline-depleted males instead showed an extension in lifespan and rejuvenated metabolic functions. Through further transcriptomic analysis, we highlight enrichment of pro-longevity pathways and genes in germline-depleted male killifish and demonstrate functional conservation of how these factors may regulate longevity in germline-depleted C. elegans. Our results therefore demonstrate that different germline manipulation paradigms can yield pronounced sexually dimorphic phenotypes, implying alternative responses to classical evolutionary tradeoffs.

genetics↗

bioRxiv2023

Stable long-term individual variation in chimpanzee technological efficiency

Using tools to access hard-to-reach and high-quality resources, such as termites, honey, and nuts, initiated a fundamental adaptive shift in human and nonhuman primate cognitive and behavioural evolution. Variation in the efficiency of extracting calorie-rich and nutrient-dense resources directly impacts energy expenditure, and potentially has significant repercussions for cultural transmission where model selection biases are employed during skill acquisition. Assessing variation in efficiency is key to understanding the evolution of complex behavioural traits in primates. Yet, individual-level differences beyond age- and sex-class in primate extractive foraging efficiency have never been investigated. Here, we used 25 years (1992- 2017) of video data of the Bossou chimpanzee community (Guinea), to investigate whether individual differences in nut-cracking efficiency exist across the life span of chimpanzees aged [≥] 6 years. Data from 3,882 oil-palm nut-cracking bouts from over 800 hours of observation were collected. We found long-term stable and reliable individual differences in four (out of five) measures of efficiency. We found no sex effect, challenging previous research on a female bias in chimpanzee tool use. These life-long differences in extractive foraging impacts daily energy budgets, which potentially have significant individual fitness and life history consequences. Additionally, the establishment of long-term individual variation in chimpanzee stone tool use has implications for interpreting archaeological records of hominins. Our findings highlight the importance of longitudinal data from long-term field sites when investigating underlying cognitive and behavioural diversity across individual lifespans and between populations.

animal behavior and cognition↗

bioRxiv2023

Keratin 17- and PKCα-dependent transient amplification of neutrophil influx after repeated stress to the skin

Neutrophils contribute to the pathogenesis of chronic inflammatory skin diseases. Little is known about the source and identity of the signals mediating their recruitment in inflamed skin. We used the phorbol ester TPA and UVB, alone or in combination, to induce sterile inflammation in mouse skin and assess whether keratinocyte-derived signals impact neutrophil recruitment. A single TPA treatment results in a neutrophil influx in the dermis that peaks at 12h and resolves within 24h. A second TPA treatment or a UVB challenge, when applied at 24h but not 48h later, accelerates, amplifies, and prolongs neutrophil infiltration. This transient amplification response (TAR) is mediated by local signals in inflamed skin, can be recapitulated in ex vivo culture, and involves the K17-dependent sustainment of protein kinase C (PKC) activity and release of neutrophil chemoattractants by stressed keratinocytes. We show that K17 binds RACK1, a scaffold essential for PKC activity. Finally, analyses of RNAseq data reveal the presence of a transcriptomic signature consistent with TAR and PKC activation in chronic inflammatory skin diseases. These findings uncover a novel, transient, and keratin-dependent mechanism that amplifies neutrophil recruitment to the skin under stress, with direct implications for inflammatory skin disorders.

immunology↗

bioRxiv2023

Alterations of the TGFb-sequestration complex member ADAMTSL1 levels are associated with muscular defects and rhabdomyosarcoma aggressiveness

Rhabdomyosarcoma (RMS) is the most frequent form of paediatric soft-tissue sarcoma and remains a medical challenge, holding in failure current therapeutic strategies. RMS shares histological features with cells of the muscle lineage and this cancer is thought to arise from malignant transformation of myogenic precursors. It has been proposed that RMS and myogenesis could represent the "Jekyll and Hyde" of skeletal muscle. The underlying idea is that some early steps of myogenic differentiation are blocked in RMS, and that understanding how the normal process has gone awry could help to decipher the biological underpinnings of tumorigenesis and tumor escape. It is widely agreed that extracellular matrix (ECM) interferes in skeletal muscle regeneration and that defects in ECM components are clinically significant. The challenge is now to decipher actors and mechanisms responsible for the transmission of signals to muscle cells and the subsequent alterations that could be associated with RMS. Using an original transgenic mice model, we show here that ADAMTSL1 is involved in skeletal muscle regeneration. As previously reported for other members of its family, ADAMTSL1 is part of the TGF-{beta}-ECM-sequestering complex and likely positively regulates TGF-{beta}-pathway activity. Last, we observed that ADAMTSL1 expression behaves as a strong prognostic factor in the aggressive fusion-positive RMS and correlates with a neural-like phenotype of tumor cells, resulting from gain of SMAD2/3/4 targets.

cancer biology↗

bioRxiv2022

Revisiting the significance of keratin expression in complex epithelia

A large group of keratin genes (n=54 in the human genome) code for intermediate filament (IF)-forming proteins and show differential regulation in epithelial cells and tissues. Keratin expression can be highly informative about the type of epithelial tissue, differentiation status of constituent cells, and biological context (e.g., normal vs. diseased settings). The foundational principles underlying the use of keratin expression to gain insight about epithelial cells and tissues primarily originated in pioneering studies conducted in the 1980s. The recent emergence of single cell transcriptomics provides an opportunity to revisit these principles and gain new insight into epithelial biology. Re-analysis of single cell RNAseq data collected from human and mouse skin has confirmed long-held views regarding the quantitative importance and pairwise regulation of specific keratin genes in keratinocytes of surface epithelia. Further, such analyses confirm and extend the notion that changes in keratin gene expression occur gradually as progenitor keratinocytes commit to and undergo differentiation, and challenge the prevailing assumption that specific keratin combinations reflect a mitotic vs. a post-mitotic, differentiating state. Our findings provide a blueprint for similar analyses in other tissues, and warrant a more nuanced approach in the use of keratin genes as biomarkers in epithelia.

bioinformatics↗

bioRxiv2022

Revealing invisible cell phenotypes with conditional generative modeling

Biological sciences, drug discovery and medicine rely heavily on cell phenotype perturbation and observation. Aside from dramatic events such as cell division or cell death, most cell phenotypic changes that keep cells alive are subtle and thus hidden from us by natural cell variability: two cells in the same condition already look different. While we show that deep learning models can leverage invisible features from microscopy images, to discriminate between close conditions, these features can yet hardly be observed and therefore interpreted. In this work, we show that conditional generative models can be used to transform an image of cells from any one condition to another, thus canceling cell variability. We visually and quantitatively validate that the principle of synthetic cell perturbation works on discernible cases such as high concentration drug treatments, nuclear translocation and golgi apparatus assays. We then illustrate its effectiveness in displaying otherwise invisible cell phenotypes triggered by blood cells under parasite infection, the presence of a disease-causing pathological mutation in differentiated neurons derived from iPSCs or low concentration drug treatments. The proposed approach, easy to use and robust, opens the door to the accessible discovery of biological and disease biomarkers.

bioinformatics↗