Search bioRxiv⌕ Search

Biology subjects

Gutierrez, J.

Publications and source records attributed to Gutierrez, J..

At least 19 recordsLinked to original sources

Whole-Proteome ESM-2 Embeddings Recover Taxonomy and Enable Geometry-Aware Triage of Foodborne Bacterial Genomes

Whole-genome sequencing (WGS) has transformed foodborne pathogen surveillance, yet time-sensitive decision-making remains constrained by computationally expensive alignment-centric workflows that scale poorly to outbreak volumes and lack built-in confidence signals. Using 21,657 GenomeTrakr-derived assemblies spanning nine food safety-relevant taxa, we represent each genome by mean-pooling per-protein embeddings from ESM-2 (480 dimensions). The resulting embedding space is dominated by taxonomic structure, exhibiting near-perfect neighborhood consistency for both species and a coarse species/pathotype-derived pathogenicity prior (mean homophily >0.99). Density-based clustering recovered species-coherent structure with high purity and bootstrap stability, while external agreement with the binary pathogenicity prior was only moderate, which is consistent with phylogenetic entanglement by design rather than embedding failure. As a within-genus stress test, kNN separates E. coli O157:H7 from non-pathogenic E. coli with [~]98% accuracy (5-fold CV), demonstrating that known pathotype annotations are preserved in the embedding geometry even among closely related genomes. We position this mean-pooling baseline relative to contextual genome language models that retain protein order or operon-scale context, and outline how embedding geometry (homophily, purity, outliers) can serve as a principled confidence layer in bio-surveillance-oriented triage pipelines.

bioinformatics↗

High-Resolution Coastal Blue Carbon Site Intelligence: A Multi-Attribute Geospatial Pipeline for National-Scale Mangrove Assessment

The voluntary blue carbon market is severely bottlenecked by outdated methodologies that apply broad, coast-level carbon averages across low-resolution spatial units, systematically failing to account for micro-site ecological realities and critical socio-political constraints. To resolve this structural deficit, this paper introduces the High-Resolution Geographically-Explicit Blue Carbon Assessment (HiGEBCA) pipeline, an innovative geospatial architecture that shifts site intelligence from monolithic raster grids to a topologically verified, hyper-dimensional polygon infrastructure. Operating on 1,601 distinct mangrove features across Colombia, the pipeline mathematically binds 47 ecological attributes to each polygon, integrating Monte Carlo uncertainty propagation, climate-stratified soil organic carbon, and rigorous biodiversity quantification spanning 293 taxon-code pairs. A diagnostic CatBoost machine learning emulator (R{superscript 2} = 0.926) deployed within the pipeline empirically demonstrates that local climate classes and biodiversity metrics drive over 96% of the variance in carbon density, proving that traditional broad biome classifications are inadequate for accurate micro-site valuation. Crucially, the HiGEBCA framework pioneers the integration of operational reality into natural capital assessment. When applied to Colombias theoretical national estate of 276,430 hectares (containing an estimated 478 million tCO2e), the pipeline executes a rigorous REDD+ white space assessment alongside hard mathematical filters for legal land tenure, armed conflict, and regulatory overlap. This strict governance filtration shatters the illusion of massive, easily accessible natural capital, systematically reducing the viable, investment-grade portfolio to a highly de-risked 4,000 to 12,000 hectares. Designed for cross-jurisdictional replication, the HiGEBCA pipeline establishes a new, transparent standard for prioritizing high-integrity blue carbon assets, providing a quantitative mandate for investors seeking to maximize climate impact, capture biodiversity premiums, and definitively mitigate operational risk.

ecology↗

Divergent climate impacts despite similar response to temperature in a widespread aerial insectivore

Climate change is shifting when animals breed1,2, but it is still not clear why some populations keep pace with warming while others fall behind3,4. Differences could arise from variation in sensitivity to temperature3 or constraints on the ability to respond to temperature. Without knowing whether populations differ in sensitivity--or in their ability to act on that sensitivity--we cannot identify which are most at risk. Using 1,555 population-years from 123 populations of tree swallows (Tachycineta bicolor), we show that populations have similar sensitivity to local temperature, advancing breeding by about one day per degree of warming. However, northern populations face tighter time constraints and greater exposure to recent warming. Northern populations have advanced laying dates the most, but still experience stronger selection for earlier breeding, especially in warm years; they have also declined most in breeding abundance. These findings show that vulnerability to climate change can arise not just from different sensitivity to warming, but from when and where populations can respond effectively. By disentangling sensitivity from timing constraints, our results support a general mechanism by which even uniformly responsive species can show uneven impacts of climate change across their ranges.

ecology↗

PlantCV v4: Image analysis software for high-throughput plant phenotyping

PlantCV is an open-source Python project aimed at developing tools to address a range of image-based, plant phenotyping questions. PlantCV has been used for more than 10 years to automate trait collection from image data and the newest release, PlantCV version 4, continues to lower the barrier to entry for users without substantial coding experience through extensive example use-case tutorials and simplified installation. In addition to usability, we document added functionality since the release of PlantCV v2, including support for more image types such as fluorescence, thermal, and hyperspectral data. Finally, we describe the development of a new subpackage focused on morphological trait measurements like leaf angle, and demonstrate its utility as compared to more manual methods of data collection. CORE IDEASO_LIPlantCV is an open-source, open-development, Python-based software package that has a new release for improved functionality and usability to make image analysis flexible and easier for researchers without a coding background. C_LIO_LIPlantCV is now capable of handling new data types that are relevant to researchers, such as thermal and hyperspectral, and has built in functionality for extracting information from these image types. C_LIO_LIThe software project aims to lower the barrier to entry into image analysis for researchers by providing numerous, versioned, interactive tutorials that cover most common use cases, particularly in plant science. C_LI

plant biology↗

Neurovascular Large artery dilatation increases the risk for Alzheimer's disease pathology

Alzheimers disease (AD) and related dementia cases are increasing globally, emphasizing the urgent need to clarify disease mechanisms for translational application in diagnoses and treatment. Vascular alterations represent a major pathological feature of AD, and beyond the well-established roles of small vessel disease and large artery atherosclerosis, our group has previously demonstrated that brain large artery dilatation is associated with elevated risk of dementia and Alzheimer pathology. The most severe manifestation of this non-atherosclerotic arterial phenotype is dolichoectasia, an enlargement of large blood vessels (Gutierrez et al., 2019; Melgarejo et al., 2024). Despite consistent epidemiological evidence across populations, the mechanistic link between arterial dilatation and AD remains poorly understood. To address this gap, we induced dolichoectasia in AppNL-G-F mice, a model of amyloid pathology, by injecting elastase into the cisterna magna. After three months, brains were examined using biochemical and immunohistochemical methods. Elastase-treated mice exhibited a significant increase in amyloid plaques in the hippocampus (p = 0.021) and cortex (p = 0.029) compared with vehicle-treated controls. Neuronal loss was evident in the CA1 region of the hippocampus (p = 0.036), with a trend towards neurodegeneration in CA3 (p = 0.055). We also observed elevated p62 in the hippocampus and cortex (p = 0.009 and p = 0.001, respectively), suggesting impaired protein or autophagic-lysosomal clearance. Although no overt increase in neuroinflammation or astrogliosis was detected at this time point, matrix metalloproteinase-9 (MMP-9) levels were trending towards elevated levels (p = 0.058). Combined, these findings indicate successful elastase-induced brain arterial dilatation accelerates AD-related pathology in AppNL-G-F mice, providing mechanistic evidence that large artery dilatation may contribute directly to Alzheimers disease progression.

neuroscience↗

Leveraging High-dimensional Seed Colorspace in Phenomic Selection Models for Herbaceous Perennial Crops

Herbaceous perennial crops, which only recently entered the domestication pipeline, offer the potential of ecological benefits in agricultural systems but remain underdeveloped, partly due to slow breeding cycles. Early-stage phenomic selection, the process of using high-dimensional secondary traits to predict target traits, may accelerate improvement. We evaluated whether seed traits derived from image scans could be used to predict germination traits in three perennial crop candidate species: sainfoin (Onobrychis viciifolia), intermediate wheatgrass (Thinopyrum intermedium), and silflower (Silphium integrifolium). Over 20,000 seeds were scanned, and PlantCV was used to extract 692 hue, saturation, and value (HSV) color features along with five morphological traits. We demonstrated that seed color, morphology, and germination traits were all influenced by maternal family, but patterns of correlation between germination traits and color and morphology traits are complex. To enable prediction from high-dimensional seed traits, we constructed relationship matrices from combinations of HSV and morphology features for use in phenomic selection models to predict germination proportion and timing. Model performance varied by trait, species, and cohort, and in many cases, predictions were significantly better than chance. HSV features, when combined with morphology, often yielded the most accurate predictions, with performance reaching a maximum of r = 0.33. These results demonstrate the potential of low-cost, image-based phenomic data to inform early-stage selection and support the development of sustainable perennial crops. Plain language summaryMany of the worlds most important crops (e.g., wheat, maize, soy) live for less than one year, leaving soil bare for many months and subject to erosion. Longer-lived (perennial) alternatives to these crops have the potential to support a more sustainable agricultural system by improving soil health and reducing the need for chemical inputs. However, perennial herbaceous plants were not domesticated by early farmers, and now lag behind annual crops in development. They take longer to breed and often lack the genetic resources needed for modern breeding approaches. In this study, we tested whether simple seed images derived from color scanners could be used to predict key traits like germination proportion and timing in emerging perennial crops. We found that seed color and shape varied by maternal family and that color, especially when combined with seed size and shape, could help predict germination performance. These predictions were significantly better than chance. This work shows that low-cost, image-based seed data can support early-stage selection in breeding programs, especially for undeveloped perennial crops, helping save time, reduce cost, and accelerate progress toward more sustainable agriculture.

plant biology↗

Clonal lineage tracing of innate immune cells in human cancer

Innate immune cells constitute the majority of the tumor microenvironment (TME), where they mediate both natural anti-tumor immunity and immunotherapy responses. While single-cell T- and B-cell receptor sequencing has provided fundamental insights into the clonal dynamics of human adaptive immunity, the lack of appropriate tools has precluded similar analysis of innate immune cells. Here, we describe a method that leverages somatic mitochondrial DNA (mtDNA) mutations to reconstruct clonal lineage relationships between single cells across cell types in native human tissues. We jointly sequenced single-cell transposase-accessible chromatin and mtDNA to profile n=124,958 cells from matched tumor, non-involved lung tissue (NILT), and peripheral blood of early-stage non-small cell lung cancer (NSCLC) patients, as well as n=93,757 cells from matched tumor and peripheral blood of ovarian cancer patients. Single-cell concomitant profiling of lineage and cell states of thousands of immune cells resolved clonality across cell types, tissue sites, and malignancies. Clonal tracing of innate immune cells demonstrates that TME-resident myeloid subsets, including macrophages and type 3 dendritic cells (DC3), are clonally linked to both circulating and tissue-infiltrating monocytes. Further, we identify distinct DC-biased and macrophage-biased myeloid clones, enriched in the tumor and NILT, respectively, and find that their circulating monocyte precursors exhibit distinct epigenetic profiles, suggesting that myeloid differentiation fate may be predetermined before TME infiltration. These results delineate the clonal pathways of intratumoral myeloid cell recruitment and differentiation in human cancer and suggest that remodeling of the tumor myeloid compartment may be peripherally programmed.

genomics↗

A role for Myosin in triggering and executing amnioserosa cell delaminations during dorsal closure.

The remodeling of epithelial tissues is a critical process in morphogenesis, often involving the apoptotic removal of individual cells while preserving tissue integrity. In Drosophila, the amnioserosa--a highly dynamic extra-embryonic tissue--undergoes extensive remodeling, culminating in its complete elimination at the end of dorsal closure. While apoptotic cell delaminations in the amnioserosa have been proposed to contribute to dorsal closure, the cellular mechanisms underlying this process remain poorly understood. In this study, we have investigated actomyosin dynamics during cell delaminations and analyzed the consequences of perturbing non-muscle Myosin activity globally in the entire tissue as well as locally in groups of cells. We found that Myosin plays an essential role in both triggering and executing cell delaminations, with high Myosin contractility promoting cell delamination via caspase activation. Additionally, our results suggest that cell delaminations are governed by both cell-autonomous Myosin dynamics and mechanical cues from the tissue environment. Together, these findings provide new insights into the regulation of epithelial cell removal and the complex interplay between apoptotic and mechanical signals during tissue remodeling.

developmental biology↗

Relationships of hematocrit concentration with dementia from a multiethnic population-based study

ObjectiveRed blood cell (RBC) concentration impacts cerebrovascular disease, yet it is unclear whether RBC concentrations relate to dementia risk, particularly in racially/ethnically diverse cohorts. We investigated whether RBC concentrations associate with incident dementia risk in a diverse population of stroke-free individuals and explored whether cerebral small vessel disease (CSVD) mediates this relationship. MethodsA longitudinal observational analysis was performed using a population-based cohort of stroke-free, older adult participants (>50 years) from the Northern Manhattan Study (NOMAS) enrolled between 2003-2008. Participants received baseline hematocrit testing, MRI neuroimaging, and cognitive assessments at baseline and long-term follow-up. Associations of baseline hematocrit as a categorical variable (low, normal [reference], and high based on laboratory reference levels) with incident dementia were assessed using Cox models adjusting for relevant covariates. Separate analyses investigated whether MRI CSVD mediated these relationships. ResultsWe studied 1207 NOMAS participants (mean age 71{+/-}9 years, 60% female, 66% Hispanic). Mean hematocrit was 41.2% ({+/-}3.8) with 16% of participants developing incident dementia. Lower hematocrit associated with increased dementia risk (adjusted hazard ratio 1.81 [1.01-3.23]) after adjusting for age, sex, race/ethnicity, education, APOE status, and comorbidities. High hematocrit was not associated with dementia risk. No interactions by sex or race/ethnicity were seen and baseline CSVD did not mediate relationships between hematocrit and dementia. ConclusionsLow hematocrit associated with dementia risk in our diverse population cohort. Further work is needed to assess mechanisms behind anemias relationship with dementia to assess whether this can serve as a trackable, preventable/treatable risk factor for dementia.

neuroscience↗

TDP43 proteinopathy exhibits disease, tissue, and context-specific cryptic splicing signatures

Mislocalization of the nuclear TAR DNA-binding protein 43 (TDP43) is a hallmark of ALS and FTD which leads to de-repression and inclusion of cryptic exons (CEs), promising biomarkers of TDP43 pathology in a spectrum of neurodegenerative diseases. However, most CEs to date have been identified from in vitro models or a single cortical FTD dataset, and little is known about cryptic splicing in the spinal cord, or within different neuronal subtypes. We meta-analyzed published bulk RNAseq datasets representing 1,778 RNAseq profiles of ALS and FTD post-mortem tissue, and in vitro models with experimentally depleted TDP43. We identified 142 cryptic splices, including 68 novel events. We found divergent cryptic splicing primarily between the spinal cord and cortex, validated in an independent ALS cohort by qPCR and supported by in situ hybridization (ISH). We also identified a set of cryptic splices observed in tissue but not in vitro, and, being present in either SOD1-ALS or MAPT-FTD subjects, likely TDP43 independent. Finally, leveraging multiple public single-nucleus RNAseq datasets of ALS and FTD motor and frontal cortex, we confirmed the elevation of cortical-enriched splices in disease and localized them to layer-specific neuronal populations. We provide a web interface to browse the meta-analysis results at https://go.roche.com/CrypticSplicingLandscape. This catalog of cryptic splices will inform efforts to develop biomarkers for tissue-specific and cell type-specific TDP43 pathology.

neuroscience↗

Phencyclidine disrupts neural coordination and cognitive control by dysregulating translation

BackgroundPhencyclidine (PCP) causes psychosis, is abused with increasing frequency, and was extensively used in antipsychotic drug discovery. PCP discoordinates hippocampal ensemble action potential discharge and impairs cognitive control in rats, but how this uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist impairs cognition remains unknown. MethodsThe effects of PCP were investigated i) on hippocampal CA1 ensemble action potential discharge in vivo in urethane-anesthetized rats and during awake behavior in mice; ii) on synaptic responses in ex vivo mouse hippocampus slices; iii) in mice on a hippocampus-dependent active place avoidance task that requires cognitive control; and iv) on activating the molecular machinery of translation in acute hippocampus slices. Mechanistic causality was assessed by comparing the PCP effects to the effects of inhibitors of protein synthesis, group-1-type metabotropic glutamate receptors (mGluR1/5), and subunit-selective NMDARs. ResultsConsistent with ionotropic actions, PCP discoordinated CA1 ensemble action potential discharge. PCP caused hyperactivity, and impaired active place avoidance, despite learning the task before PCP. Consistent with metabotropic actions, PCP exaggerated protein-synthesis dependent DHPG-induced mGluR1/5-stimulated long-term synaptic depression (LTD). Pretreatment with anisomycin or the mGluR1/5-antagonist MPEP, both of which repress translation, prevented the PCP-induced discoordination, and the cognitive and sensorimotor impairments. PCP as well as the NR2A-containing NMDAR-antagonist NVP-AAM077 unbalanced translation that engages the AKT, mTOR and 4EBP1 translation machinery and increased protein synthesis, whereas the NR2B-containing antagonist Ro25-6981 did not. ConclusionsPCP dysregulates translation, acting through NR2A-containing NMDAR subtypes, recruiting mGluR1/5 signaling pathways, leading to the neural discoordination that is central to the cognitive and sensorimotor impairments.

neuroscience↗

A system-level view on the function of natural eukaryotic biomes through taxonomically resolved metabolic pathway profiling

High-throughput sequencing of environmental samples has dramatically improved our understanding of the molecular activities of complex microbial communities in their natural environments. For instance, by enabling taxonomic profiling and differential gene expression analysis, microbiome studies have revealed intriguing associations between community structure and ecosystem functions. However, the effectiveness of sequence data analysis to characterize the functioning of microbial ecosystems at the systems level (e.g. metabolic pathways) and at high taxonomic resolution has thus far been limited by the quality and scope of reference sequence databases. In this work, we applied state of the art bioinformatics tools to leverage publicly available genome/gene sequences for a wide array of (mostly eukaryotic) planktonic organisms to build a customized protein sequence database. Based on this, our goal is to conduct a systems-level interrogation of environmental samples, which can effectively augment the insights obtained through traditional gene-centric analysis (i.e. analysis of single gene expression profiles at the genome-wide level). To achieve this, we utilized the popular HUMAnN pipeline, which has proven effective at delineating taxon-specific metabolic pathways that may be actively contributing to the overall functioning of a microbiome. To test the efficacy of our database customization for mapping metabolic pathway activities in complex planktonic ecosystems, we reanalyzed previously published metatranscriptome datasets derived from different marine environments. Our results demonstrate that database customization can substantially improve our ability to quantitatively assess core metabolic processes across taxonomically diverse marine microbiomes, which have so far remained largely uncharacterized at the systems level. By further expanding on the taxonomic and functional complexity of our database with newly released high-quality genome assemblies and gene catalogs for marine microbes, we aim to improve our ability to map the molecular traits that drive changes in the composition and functioning of marine planktonic networks through space and time.

systems biology↗

Dynamic cybergenetic control of bacterial co-culturecomposition via optogenetic feedback

Communities of microbes play important roles in natural environments and hold great potential for deploying division-of-labor strategies in synthetic biology and bioproduction. However, the difficulty of controlling the composition of microbial consortia over time hinders their optimal use in many applications. Here, we present a fully automated, high-throughput platform that combines real-time measurements and computer-controlled optogenetic modulation of bacterial growth to implement precise and robust compositional control of a two-strain E. coli community. Additionally, we develop a general framework for dynamic modeling of synthetic genetic circuits in the physiological context of E. coli and use a host-aware model to determine the optimal control parameters of our closed-loop compositional control system. Our platform succeeds in stabilizing the strain ratio of multiple parallel co-cultures at arbitrary levels and in changing these targets over time, opening the door for the implementation of dynamic compositional programs in synthetic bacterial communities.

synthetic biology↗

Experimental effects of within-brood genetic variation on parasite resistance in a wild bird host

Hosts can differ in parasite susceptibility across individuals, populations, and species. Genetic variation can influence parasite susceptibility by affecting host resistance to parasitism. For example, genetic variation among related individuals, such as within broods of offspring, might be a key factor influencing within-brood resistance to ectoparasitism. The goal of this study was to determine if within-brood variation of eastern bluebirds (Sialia sialis) affects susceptibility to ectoparasitic blowflies (Protocalliphora sialia). To address the goal, we conducted a partial cross-fostering study for which half of the nestlings were cross-fostered (experimental) or not (control). Nestling physiology (i.e., glucose, hemoglobin, and parasite-specific IgY antibody levels), morphometrics (i.e., mass, tarsus length, bill length, and first primary feather), survival, nestling status (resident versus fostered), and sex were characterized. We also quantified parasite abundance, life stage, and pupal size. We found that experimental nests had fewer parasites and more larvae than pupae compared to control nests, which suggest that within-brood genetic variation affects parasite abundance. However, this effect was driven by the sex ratio with the experimental nests, with female-biased nests having fewer parasites than male-biased nests. Treatment did not affect nestling morphometrics, physiology, or survival at the nest level. Within experimental nests, resident females had significantly higher hemoglobin levels when compared to fostered females. Resident and fostered males and fostered females had significantly higher glucose levels than resident females. Together, these results suggest that resident females were fed upon less than fostered females and may have been less stressed than males and fostered females. Overall, our study demonstrates the importance of considering within-brood variation and nestling sex in understanding host-parasite interactions.

ecology↗

Independent origins of the Golgi phosphoprotein 3 oncoprotein gene

Golgi phosphoprotein 3 (GOLPH3) was the first reported oncoprotein of the Golgi apparatus. It was identified as an evolutionarily conserved protein upon its discovery about 20 years ago, but its function remains puzzling in normal and cancer cells. The GOLPH3 gene is part of a group of genes that also includes the GOLPH3L gene. Because cancer has deep roots in multicellular evolution, studying the evolution of the GOLPH3 gene family in non-model species represents an opportunity to identify new model systems that could help better understand the biology behind this group of genes. The main goal of this study is to explore the evolution of the GOLPH3 gene family in birds as a starting point to understand the evolutionary history of this oncoprotein. We identified a repertoire of three GOLPH3 genes in birds. We found duplicated copies of the GOLPH3 gene in all main groups of birds other than paleognaths, and a single copy of the GOLPH3L gene. We suggest there were at least three independent origins for GOLPH3 duplicates. Amino acid divergence estimates show that most of the variation is located in the N-terminal region of the protein. Our transcript abundance estimations show that one paralog is highly and ubiquitously expressed, and the others were variable. Our results are an example of the significance of understanding the evolution of the GOLPH3 gene family, especially for unraveling its structural and functional attributes.

evolutionary biology↗

Development and pre-clinical characterization of two therapeutic equine formulations towards SARS-CoV-2 proteins for the potential treatment of COVID-19

In the current global emergency due to SARS-CoV-2 outbreak, passive immunotherapy emerges as a promising treatment for COVID-19. Among animal-derived products, equine formulations are still the cornerstone therapy for treating envenomations due to animal bites and stings. Therefore, drawing upon decades of experience in manufacturing snake antivenom, we developed and preclinically evaluated two anti-SARS-CoV-2 polyclonal equine formulations as potential alternative therapy for COVID-19. We immunized two groups of horses with either S1 (anti-S1) or a mixture of S1, N, and SEM mosaic (anti-Mix) viral recombinant proteins. Horses reached a maximum anti-viral antibody level at 7 weeks following priming, and showed no major adverse acute or chronic clinical alterations. Two whole-IgG formulations were prepared via hyperimmune plasma precipitation with caprylic acid and then formulated for parenteral use. Both preparations had similar physicochemical and microbiological quality and showed ELISA immunoreactivity towards S1 protein and the receptor binding domain (RBD). The anti-Mix formulation also presented immunoreactivity against N protein. Due to high anti-S1 and anti-RBD antibody content, final products exhibited high in vitro neutralizing capacity of SARS-CoV-2 infection, 80 times higher than a pool of human convalescent plasma. Pre-clinical quality profiles were similar among both products, but clinical efficacy and safety must be tested in clinical trials. The technological strategy we describe here can be adapted by other producers, particularly in low- and middle-income countries.

microbiology↗

Myomixer is expressed during embryonic and post-larval hyperplasia, muscle regeneration and fusion of myoblats in rainbow trout (Oncorhynchus mykiss)

1.In contrast to mice or zebrafish, trout exhibits post-larval muscle growth through hypertrophy and formation of new myofibers (hyperplasia). The muscle fibers are formed by the fusion of mononucleated cells (myoblasts) regulated by several muscle-specific proteins such as myomaker or myomixer. In this work, we identified a unique gene encoding a myomixer protein of 77 amino acids (aa) in the trout genome. Sequence analysis and phylogenetic tree, showed moderate conservation of the overall protein sequence across teleost fish (61% of aa identity between trout and zebrafish myomixer sequences). Nevertheless, the functionally essential motif, AxLyCxL is perfectly conserved in all studied sequences of vertebrates. Using in situ hybridization, we observed that myomixer was highly expressed in the embryonic myotome, particularly in the hyperplasic area. Moreover, myomixer remained readily expressed in white muscle of juvenile (1 and 20 g) although its expression decreased in mature fish. We also showed that myomixer is up-regulated during muscle regeneration and in vitro myoblasts fusion. Together, these data indicate that myomixer expression is consistently associated with the formation of new myofibers during somitogenesis, post-larval growth and muscle regeneration in trout.

cell biology↗

A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic

Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.

cell biology↗