Biology subjects

Pardo, J.

Publications and source records attributed to Pardo, J..

16 recordsLinked to original sources

bioRxiv2026

APOBEC3B mRNA Expression in Breast Cancer Correlates with Genomic Mutational Signatures

Despite advances in screening and treatment, breast cancer remains a leading cause of cancer-related mortality. APOBEC enzymes, particularly APOBEC3B (A3B), are upregulated in many cancers, contributing to a characteristic C-to-T mutational signature found in 30-50% of breast cancers. However, the relationship between A3B mutational signatures and A3B expression across subtypes, and the resulting potential biologic consequences, have not been fully defined. Using TCGA and ICGC datasets, we analyzed DNA and RNA expression data to assess the relationship between A3B mRNA expression and APOBEC enrichment scores. Pathway enrichment analyses (KEGG, GO, Reactome) were performed to identify biological processes associated with high A3B expression, specifically stratifying by breast cancer intrinsic subtypes (HR+/HER2-, HR+/HER2+, HR-/HER2+, and TNBC). Over 64% of tumors with enriched A3B mutational genomic signatures demonstrated above-median A3B mRNA expression (p < 0.001). High A3B-expressing tumors exhibited specific alterations in drug metabolism pathways. Notably, we observed reduced expression of CYP2D6 and CYP3A isoforms which is required for the conversion of tamoxifen to its active metabolites. Conversely, genes involved in pyrimidine metabolism, including IMPDH1, NME1, TK1, and DPYS, were downregulated in high A3B tumors. Elevated A3B expression correlates with mutational signatures and may contribute to impaired tamoxifen activation and endocrine resistance, while concurrently creating metabolic vulnerabilities to pyrimidine-based chemotherapies. Targeting A3B or exploiting these metabolic dependencies may improve therapeutic response in selected patient subsets.

cancer biology↗

bioRxiv2025

Stress-responsive transcription factor families are key components of the core abiotic stress response in maize

Abiotic stresses, including drought, salt, heat, cold, flooding, and low nitrogen, have devastating impacts on agriculture and are increasing in frequency globally due to climate change. Plants can experience multiple abiotic stresses simultaneously or sequentially within a single growing season, and combinatorial stresses elicit shared or overlapping molecular and physiological responses. Here, we searched for core stress responsive genes in maize across diverse abiotic stressors through meta-analysis of public RNAseq data. Our analysis revealed significant heterogeneity in gene expression across datasets due to factors such as tissue type, genotype, and experimental conditions, which we mitigated through batch correction. Using nearly 1,900 RNAseq samples with both traditional set operations and a novel random forest machine learning approach, we identified a core set of 744 stress-responsive genes across the six stresses. These core genes are enriched in transcription factors, including stress-responsive families such as AP2/ERF-ERF, NAC, bZIP, HSF, and C2C2-CO-like. Co-expression network analysis demonstrated that these core TFs are co-expressed with stress-specific peripheral genes, supporting their role in regulating both generalized and stress-specific responses. Our results suggest that maize employs a conserved yet flexible transcriptional strategy to respond to abiotic stresses, with core TFs acting as potential regulators of both universal and stress-specific pathways. These findings provide a valuable resource for understanding stress tolerance mechanisms and for guiding future breeding and engineering efforts to enhance maize resilience under climate change.

plant biology↗

bioRxiv2024

Lack of neuroprotection after systemic administration of the soluble TNF inhibitor XPro1595 in an rAAV6-α-Syn+PFFs-induced rat model for Parkinson's disease

Parkinsons disease (PD) is characterized by dopaminergic neurodegeneration, -Synuclein (-Syn) pathology, and inflammation. Microglia in the substantia nigra pars compacta (SNpc) upregulate major histocompatibility complex class II (MHCII), and variants in genes encoding MHCII affect PD risk. Additionally, elevated TNF levels and -Syn-reactive T cells in circulation suggest a strong link between innate and adaptive immune responses in PD. We have previously reported that reduced levels of the class II transactivator, the master regulator of MHCII expression, increases susceptibility to -Syn-induced PD-like pathology in rats and are associated with higher serum levels of soluble TNF (sTNF). Here, we demonstrate that inhibiting sTNF with a dominant-negative TNF variant, XPro1595, known to be neuroprotective in endotoxin- and toxin-induced neurodegeneration models, fails to protect against robust -Syn-induced PD-like pathology in rats. We used a model combining rAAV-mediated -Syn overexpression in SNpc with striatal injection of -Syn preformed fibrils two weeks later. Systemic XPro1595 treatment was initiated one-week post-rAAV--Syn. We observed up to 70% loss of striatal dopaminergic fibers without treatment, and no protective effects on dopaminergic neurodegeneration after XPro1595 administration. Pathological -Syn levels as well as microglial and astrocytic activation were not reduced in SNpc or striatum following XPro1595 treatment. An increase in IL-6 and IL-1{beta} levels in CSF was observed in rats treated with XPro1595, possibly explaining a lack of protective effects following treatment. Our results highlight the need to determine the importance of timing of treatment initiation, which is crucial for future applications of sTNF therapies in PD patients.

neuroscience↗

bioRxiv2024

Variability in drought gene expression datasets highlight the need for community standardization

Physiologically relevant drought stress is difficult to apply consistently, and the heterogeneity in experimental design, growth conditions, and sampling schemes make it challenging to compare water deficit studies in plants. Here, we re-analyzed hundreds of drought gene expression experiments across diverse model and crop species and quantified the variability across studies. We found that drought studies are surprisingly uncomparable, even when accounting for differences in genotype, environment, drought severity, and method of drying. Many studies, including most Arabidopsis work, lack high-quality phenotypic and physiological datasets to accompany gene expression, making it impossible to assess the severity or in some cases the occurrence of water deficit stress events. From these datasets, we developed supervised learning classifiers that can accurately predict if RNA-seq samples have experienced a physiologically relevant drought stress, and suggest this can be used as a quality control for future studies. Together, our analyses highlight the need for more community standardization, and the importance of paired physiology data to quantify stress severity for reproducibility and future data analyses.

plant biology↗

bioRxiv2022

Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair

Cell death coordinates repair programs following pathogen attack and tissue injury. However, aberrant cell death can interfere with such programs and cause organ failure. cFLIP is a crucial regulator of cell death and a substrate of Caspase-8. Yet, the physiological role of cFLIP cleavage by Caspase-8 remains elusive. Here, we discovered an essential role for cFLIP cleavage in restraining cell death in different pathophysiological scenarios. Mice expressing a cleavage-resistant cFLIP mutant, CflipD377A, exhibited increased sensitivity to SARS-CoV-induced lethality, impaired skin wound healing and increased tissue damage caused by Sharpin deficiency. In vitro, abrogation of cFLIP cleavage sensitizes cells to TNF-induced necroptosis and apoptosis by favoring complex-II formation. Mechanistically, the cell death-sensitizing effect of the D377A mutation depends on Gln(Q)469. These results reveal a crucial role for cFLIP cleavage in controlling the amplitude of cell death responses occurring upon tissue stress, to ensure the execution of repair programs.

cell biology↗

bioRxiv2022

Cross-species predictive modeling reveals conserved drought responses between maize and sorghum

Drought tolerance is a highly complex trait controlled by numerous interconnected pathways with substantial variation within and across plant species. This complexity makes it difficult to distill individual genetic loci underlying tolerance, and to identify core or conserved drought responsive pathways. Here, we collected drought physiology and gene expression datasets across diverse genotypes of the C4 cereals sorghum and maize and searched for signatures defining water deficit responses. Differential gene expression identified few overlapping drought associated genes across sorghum genotypes, but using a predictive modeling approach, we found a shared core drought response across development, genotype, and stress severity. Our model had similar robustness when applied to datasets in maize, reflecting a conserved drought response between sorghum and maize. The top predictors are enriched in functions associated with various abiotic stress responsive pathways as well as core cellular functions. These conserved drought response genes were less likely to contain deleterious mutations than other gene sets, suggesting that core drought responsive genes are under evolutionary and functional constraints. Our findings support a broad evolutionary conservation of drought responses in C4 grasses regardless of innate stress tolerance, which could have important implications for developing climate resilient cereals. Significance StatementDrought is a complex and variable stress that is difficult to quantify and link to underlying mechanisms both within and across species. Here, we developed a predictive model to classify drought stress responses in sorghum and identify important features that are responsive to water deficit. Our model has high predictive accuracy across development, genotype, and stress severity, and the top features are enriched in genes related to classical stress responses and have functional and evolutionary conservation. We applied this sorghum trained model to maize, and observed similar predictive accuracy of drought responses, supporting transfer learning across plant species. Our findings suggest there are deeply conserved drought responses across C4 grasses that are unrelated to tolerance.

plant biology↗

bioRxiv2022

The topological shape of gene expression across the evolution of flowering plants

Since they emerged ~125 million years ago, flowering plants have evolved to dominate the terrestrial landscape and survive in the most inhospitable environments on earth. At their core, these adaptations have been shaped by changes in numerous, interconnected pathways and genes that collectively give rise to emergent biological phenomena. Linking gene expression to morphological outcomes remains a grand challenge in biology, and new approaches are needed to begin to address this gap. Here, we implemented topological data analysis (TDA) to summarize the high dimensionality and noisiness of gene expression data using lens functions that delineate plant tissue and stress responses. Using this framework, we created a topological representation of the shape of gene expression across plant evolution, development, and environment for the phylogenetically diverse flowering plants. The TDA-based Mapper graphs form a well-defined gradient of tissues from leaves to seeds, or from healthy to stressed samples, depending on the lens function. This suggests there are distinct and conserved expression patterns across angiosperms that delineate different tissue types or responses to biotic and abiotic stresses. Genes that correlate with the tissue lens function are enriched in central processes such as photosynthetic, growth and development, housekeeping, or stress responses. Together, our results highlight the power of TDA for analyzing complex biological data and reveal a core expression backbone that defines plant form and function. Significance statementA grand challenge in biology is to link gene expression to phenotypes across evolution, development, and the environment, but efforts have been hindered by biological complexity and dataset heterogeneity. Here, we implemented topological data analysis across thousands of gene expression datasets in phylogenetically diverse flowering plants. We created a topological representation of gene expression across plants and observed well-defined gradients of tissues from leaves to seeds, or from healthy to environmentally stressed. Using this framework, we identified a core and deeply conserved expression backbone that defines plant form and function, with key patterns that delineate plant tissues, abiotic, and biotic stresses. Our results highlight the power of topological approaches for analyzing complex biological datasets.

plant biology↗

bioRxiv2022

Predicting leaf traits across functional groups using reflectance spectroscopy

O_LIPlant ecologists use functional traits to describe how plants respond to and influence their environment. Reflectance spectroscopy can provide rapid, non-destructive estimates of leaf traits, but it remains unclear whether general trait-spectra models can yield accurate estimates across functional groups and ecosystems. C_LIO_LIWe measured leaf spectra and 22 structural and chemical traits for nearly 2000 samples from 104 species. These samples span a large share of known trait variation and represent several functional groups and ecosystems. We used partial least-squares regression (PLSR) to build empirical models for estimating traits from spectra. C_LIO_LIWithin the dataset, our PLSR models predicted traits like leaf mass per area (LMA) and leaf dry matter content (LDMC) with high accuracy (R2>0.85; %RMSE<10). Models for most chemical traits, including pigments, carbon fractions, and major nutrients, showed intermediate accuracy (R2=0.55-0.85; %RMSE=12.7-19.1). Micronutrients such as Cu and Fe showed the poorest accuracy. In validation on external datasets, models for traits like LMA and LDMC performed relatively well, while carbon fractions showed steep declines in accuracy. C_LIO_LIWe provide models that produce fast, reliable estimates of several widely used functional traits from leaf reflectance spectra. Our results reinforce the potential uses of spectroscopy in monitoring plant function around the world. C_LI

ecology↗

bioRxiv2022

The complex octoploid Craterostigma genome and tissue-specific mechanisms underlying desiccation tolerance

Resurrection plants can survive prolonged anhydrobiosis, and desiccation tolerance has evolved recurrently across land plants as a common adaptation for survival in regions with seasonal drying. Craterostigma plantagineum was among the first model resurrection plants, and many of the genetic mechanisms underlying desiccation tolerance were discovered in this important system. Here, we analyzed the complex, octoploid Craterostigma (C. plantagineum) genome and surveyed spatial and temporal expression dynamics to identify genetic elements underlying desiccation tolerance. Homeologous genes within the Craterostigma genome have divergent expression profiles, suggesting the subgenomes contribute differently to desiccation tolerance traits. The Craterostigma genome contains almost 200 tandemly duplicated early light induced proteins (ELIPs), a hallmark trait of desiccation tolerance, with massive upregulation under water deficit. We identified a core network of desiccation responsive genes across all tissues but observed almost entirely unique expression dynamics in each tissue during recovery. Roots and leaves have differential responses related to light and photoprotection, autophagy, and nutrient transport, reflecting their divergent functions. Our findings highlight a universal set of likely ancestral desiccation tolerance mechanisms to protect cellular macromolecules under anhydrobiosis, with secondary adaptations related to tissue function.

plant biology↗

bioRxiv2021

Opposing roles of Granzymes A and B in the immune response to intestinal infection

Intestinal intraepithelial T lymphocytes (IEL) constitutively express high amounts of the cytotoxic proteases Granzymes (Gzm) A and B and are therefore thought to protect the intestinal epithelium against infection by killing infected epithelial cells. However, the role of IEL granzymes in a protective immune response has yet to be demonstrated. We show that GzmA and GzmB are required to protect mice against oral, but not intravenous, infection with Salmonella enterica serovar Typhimurium, consistent with an intestine-specific role. IEL-intrinsic granzymes mediate the protective effects by controlling intracellular bacterial growth and aiding in cell-intrinsic pyroptotic cell death of epithelial cells. Surprisingly, we found that both granzymes play non- redundant roles. GzmB-/- mice carried significantly lower burdens of Salmonella, as predominant GzmA-mediated cell death effectively reduced bacterial translocation across the intestinal barrier. Conversely, in GzmA-/-mice, GzmB-driven apoptosis favored luminal Salmonella growth by providing nutrients, while still reducing translocation across the epithelial barrier. Together, the concerted actions of both GzmA and GzmB balance cell death mechanisms at the intestinal epithelium to provide optimal control that Salmonella cannot subvert. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/467595v3_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@2b2c9corg.highwire.dtl.DTLVardef@7de81eorg.highwire.dtl.DTLVardef@1209d2org.highwire.dtl.DTLVardef@42dffb_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2020

First-described recently discovered non-toxic vegetal-derived furocoumarin preclinical efficacy against SARS-CoV-2: a promising antiviral herbal drug.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiology of coronavirus disease 2019 (COVID19) pandemic. ICEP4 purified compound (ICEP4) is a recently discovered furocoumarin-related purified compound derived from the roots and seeds of Angelica archangelica (herbal drug). ICEP4-related herbal preparations have been extensively used as active herbal ingredients in traditional medicine treatments in several European countries. Extraction method of patent pending ICEP4 (patent application no. GB2017123.7) has previously shown strong manufacturing robustness, long-lasting stability, and repeated chemical consistency. Here we show that ICEP4 presents a significant in vitro cytoprotective effect in highly virulent-SARS-CoV-2 challenged Vero E6 cellular cultures, using doses of 34.5 and 69 M. No dose-related ICEP4 toxicity was observed in Vero E6 cells, M0 macrophages, B, CD4+ T and CD8+ T lymphocytes, Natural Killer (NK) or Natural Killer T (NKT) cells. No dose-related ICEP4 inflammatory response was observed in M0 macrophages quantified by IL6 and TNF release in cell supernatant. No decrease in survival rate was observed after either 24 hr acute or 21-day chronic exposure in in vivo toxicity studies performed in C. elegans. Therefore, ICEP4 toxicological profile has demonstrated marked differences compared to others vegetal furocoumarins. Successful ICEP4 doses against SARS-CoV-2-challenged cells are within the maximum threshold of toxicity concern (TTC) of furocoumarins as herbal preparation, stated by European Medicines Agency (EMA). The characteristic chemical compounding of ICEP4, along with its safe TTC, allow us to assume that the first-observation of a natural antiviral compound has occurred. The potential druggability of a new synthetic ICEP4-related compound remains to be elucidated. However, well-established historical use of ICEP4-related compounds as herbal preparations may point towards an already-safe, widely extended remedy, which may be ready-to-go for large-scale clinical trials under the EMA emergency regulatory pathway. To the best of the authors knowledge, ICEP4-related herbal drug can be postulated as a promising therapeutic treatment for COVID19.

pharmacology and toxicology↗

bioRxiv2020

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis.

Sepsis is a serious syndrome characterised by a dysregulated systemic inflammatory response. Here we have analysed the role and the therapeutic potential of Granzyme A (GzmA) in the pathogenesis of peritoneal sepsis using the Cecal Ligation and Puncture (CLP) polymicrobial sepsis model and samples from humans undergoing abdominal sepsis. Elevated GzmA was observed in serum from patients with abdominal sepsis suggesting that GzmA plays an important role in this pathology. In the CLP model GzmA deficient mice, or WT mice treated with an extracellular GzmA inhibitor, showed increased survival, which correlated with a reduction in proinflammatory markers in both serum and peritoneal lavage fluid. GzmA deficiency did not influence bacterial load in blood and spleen indicating that GzmA has no role in bacterial control. Mechanistically, we found that extracellular active GzmA acts as a proinflammatory mediator in macrophages by inducing the TLR4-dependent expression of IL-6 and TNF. Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis, and suggest that it could be targeted for treatment of this severe pathology.

immunology↗

bioRxiv2019

Intertwined signatures of desiccation and drought tolerance in grasses

Grasses are among the most resilient plants and some can survive prolonged desiccation in semi-arid regions with seasonal rainfall. This vegetative desiccation tolerance has arisen independently multiple times within the grass family, but the genetic elements that differentiate desiccation tolerant and sensitive grasses are largely unknown. Here we leveraged comparative genomic approaches with the resurrection grass Eragrostis nindensis and the closely related desiccation sensitive cereal Eragrostis tef to identify changes underlying desiccation tolerance. We extended the analyses to include the grasses maize, sorghum, rice, and the model desiccation tolerant grass Oropetium thomaeum to identify broader evolutionary conservation and divergence. We identified changes in chromatin architecture and expression dynamics related to desiccation in E. nindensis. It was previously hypothesized that transcriptional re-wiring of seed desiccation pathways confers vegetative desiccation tolerance. We demonstrate that the majority of seed dehydration related genes show similar expression patterns in leaves of desiccation tolerant and sensitive species during dehydration. However, we discovered a small set of orthologs with expression specific to leaves of desiccation tolerant species, and seeds of sensitive species. This supports a nuanced role of seed-related genes where many overlap with typical drought responses but some crucial genes are desiccation specific in resurrection plants.

plant biology↗

bioRxiv2019

Transcriptome-based prediction of complex traits in maize

The ability to predict traits from genome-wide sequence information (Genomic Prediction, GP), has improved our understanding of the genetic basis of complex traits and transformed breeding practices. Transcriptome data may also be useful for GP. However, it remains unclear how well transcript levels can predict traits, particularly when traits are scored at different development stages. Using maize genetic markers and transcript levels from seedlings to predict mature plant traits, we found transcript and genetic marker models have similar performance. Surprisingly, genetic markers important for predictions were not close to or identified as regulatory variants for important transcripts. Thus, transcript levels are predictive not simply due to genetic variation. Furthermore, genetic marker models identified only one of 14 benchmark flowering time genes, while transcript models identified five. Our findings highlight that transcriptome data is useful for GP and can provide a link between traits and variation that cannot be readily captured at the sequence level.

genetics↗

bioRxiv2019

Exceptional subgenome stability and functional divergence in allotetraploid teff, the primary cereal crop in Ethiopia

Teff (Eragrostis tef) is a cornerstone of food security in the Horn of Africa, where it is prized for stress resilience, grain nutrition, and market value. Despite its overall importance to small-scale farmers and communities in Africa, teff suffers from low production compared to other cereals because of limited intensive selection and molecular breeding. Here we report a chromosome-scale genome assembly of allotetraploid teff (variety Dabbi) and patterns of subgenome dynamics. The teff genome contains two complete sets of homoeologous chromosomes, with most genes maintained as syntenic gene pairs. Through analyzing the history of transposable element activity, we estimate the teff polyploidy event occurred [~]1.1 million years ago (mya) and the two subgenomes diverged [~]5.0 mya. Despite this divergence, we detected no large-scale structural rearrangements, homoeologous exchanges, or bias gene loss, contrasting most other allopolyploid plant systems. The exceptional subgenome stability observed in teff may enable the ubiquitous and recurrent polyploidy within Chloridoideae, possibly contributing to the increased resilience and diversification of these grasses. The two teff subgenomes have partitioned their ancestral functions based on divergent expression patterns among homoeologous gene pairs across a diverse expression atlas. The most striking differences in homoeolog expression bias are observed during seed development and under abiotic stress, and thus may be related to agronomic traits. Together these genomic resources will be useful for accelerating breeding efforts of this underutilized grain crop and for acquiring fundamental insights into polyploid genome evolution.

plant biology↗

bioRxiv2018

A chromosome scale assembly of the model desiccation tolerant grass Oropetium thomaeum

Oropetium thomaeum is an emerging model for desiccation tolerance and genome size evolution in grasses. A high-quality draft genome of Oropetium was recently sequenced, but the lack of a chromosome scale assembly has hindered comparative analyses and downstream functional genomics. Here, we reassembled Oropetium, and anchored the genome into ten chromosomes using Hi-C based chromatin interactions. A combination of high-resolution RNAseq data and homology-based gene prediction identified thousands of new, conserved gene models that were absent from the V1 assembly. This includes thousands of new genes with high expression across a desiccation timecourse. The sorghum and Oropetium genomes have a surprising degree of chromosome-level collinearity, and several chromosome pairs have near perfect synteny. Other chromosomes are collinear in the gene rich chromosome arms but have experienced pericentric translocations. Together, these resources will be useful for the grass comparative genomic community and further establish Oropetium as a model resurrection plant.

plant biology↗