Biology subjects

Rivas, C.

Publications and source records attributed to Rivas, C..

10 recordsLinked to original sources

bioRxiv2026

Potent broad-spectrum antiviral activity of the marine natural product Plitidepsin

Viruses pose a critical global health threat, yet therapeutic options remain limited. Finding drugs with broad-spectrum antiviral activity is essential to confront this threat. Here, we investigated whether plitidepsin, a marine-derived anticancer drug targeting the host eukaryotic elongation factor 1A (eEF1A), has such broad-spectrum activity. Using in vitro infection models and complementary assays (MTT, plaque-forming assays, RT-qPCR, Western blot, flow cytometry), we demonstrated that plitidepsin exhibits potent dose-dependent antiviral activity against Mayaro virus (MAYV) and Chikungunya virus (CHIKV). The compound achieved 4-6 log10 reduction in viral titers at nanomolar concentrations across multiple cell lines and viral strains. Plitidepsin protected human dermal fibroblasts from viral cytopathic effects and disrupted both entry and post-entry replication stages by suppressing viral protein expression (E1, nsP1) and RNA synthesis. The compound also demonstrated antiviral activity against other medically important arboviruses, including Una, Punta Toro, Zika, and Oropouche viruses, as well as RNA and DNA viruses such as influenza A virus, vesicular stomatitis virus, and human cytomegalovirus. These findings establish plitidepsin as a potent host-directed antiviral agent with reduced likelihood of resistance development and therapeutic potential against multiple viral families.

microbiology↗

bioRxiv2025

Broad-spectrum antiviral activity of the synthetic rocaglate zotatifin against multiple viruses

Viruses pose a significant threat to global public health, yet therapeutic options are limited. Zotatifin, a synthetic rocaglate, targets eukaryotic initiation factor 4A (eIF4A), thereby inhibiting viral protein synthesis and triggering an interferon response. Whether zotatifin exhibits broad-spectrum antiviral activity is unknown. Here we evaluated zotatifins cytotoxicity using the MTT method and its antiviral activity using plaque-forming assays, Western blot analysis, immunofluorescence, and flow cytometry across multiple cell lines and virus strains. Zotatifin demonstrated better tolerability than rocaglates rocaglamide A and CR-1-31-B. The compound exhibited potent, dose-dependent inhibition of the Mayaro virus, achieving greater than a 4-log reduction in viral titers at a 50 nM dose, regardless of the cell line or virus strain tested. In addition, zotatifin was effective to inhibit multiple arboviruses (Chikungunya, Una, and Zika), influenza A virus, vesicular stomatitis virus, and vaccinia virus. Zotatifin down-regulated viral protein synthesis for all viruses tested and analysis of gene expression using RT-qPCR revealed activation of the type I interferon pathway in zotatifin-treated cells. Taken together, these results suggest that zotatifin exhibits broad-spectrum antiviral activity against five virus families, likely via several molecular mechanisms. This work supports the potential therapeutic use of zotatifin as a pan-antiviral drug in humans.

microbiology↗

bioRxiv2025

Disruption of the FGFR1-FGF23-Phosphate Axis and Targeted Therapy in a Murine Model of Osteoglophonic Dysplasia

Osteoglophonic Dysplasia (OGD) is an autosomal dominant skeletal dysplasia characterized by impaired bone growth resulting in short stature, severe craniofacial abnormalities, and in some patients FGF23-mediated hypophosphatemia. It is caused by gain-of-function variants in FGFR1, particularly in or near the transmembrane domain of the receptor. We used CRISPR in mice to knock-in the FGFR1 p.N330I variant, chosen based on its association with FGF23 excess. Skeletal phenotyping of this Fgfr1+/N330I model demonstrated markedly reduced body weight and naso-anal length, shortened long bones, and craniosynostosis, all hallmarks of the human disease. Mutant mice exhibited profound microarchitectural changes in cortical bone and severe disorganization of the growth plate and articular cartilage, driven by decreased cell proliferation and increased apoptosis in skeletal tissues. In addition to osteochondrodysplasia, we noted dramatic increases in plasma FGF23 and hypophosphatemia, driven by upregulated Fgf23 expression and protein levels in bone, with consequent undermineralization. An in vivo ossicle assay allowed longitudinal evaluation of mineral metabolism. We modulated the signaling pathway by repurposing an inhibitor of the overactive receptor, infigratinib, resulting in partial restoration of naso-anal length in treated mutant mice. This first model of OGD offers insights into the disease pathogenesis and open avenues for targeted therapeutic strategies.

molecular biology↗

bioRxiv2024

Transcriptional repression of SOX2 by p53 in cancer cells regulates cell identity and migration

During cancer development and progression, many genetic alterations lead to the acquisition of novel features that confer selective advantage to cancer cells and that resemble developmental programs. SOX2 is one of the key pluripotency transcription factors, expressed during embryonic development and active in adult stem cells. In cancer, SOX2 is frequently dysregulated and associated with tumor stemness and poor patient survival. SOX2 expression is suppressed in differentiated cells by tumor suppressor proteins that form a transcriptional repressive complex. We previously identified some of these proteins and found that their absence combined with deficiency in Trp53, leads to maximal dysregulated expression of Sox2. Using cancer cell lines of different origin and with different p53 status, we show here that manipulating TP53 to restore or decrease its activity results in repression or induction of SOX2, respectively. Mechanistically, we observed that the regulation of SOX2 expression by TP53 is transcriptional and identified Trp53 bound to the promoter region and the SRR2 enhancer of Sox2. Forcing high levels of SOX2 in cancer cells leads to morphological changes that molecularly correspond to the acquisition of a more mesenchymal phenotype correlating with an increased migratory capacity. Finally, the analysis of human breast cancer samples shows that this correlation between TP53 status, levels of expression of SOX2 and a more metastatic phenotype is also observed in cancer patients. Our results support the notion that lack of TP53 in tumor cells results in deregulated expression of developmental gene SOX2 with phenotypic consequences related with increased malignization. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/623640v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@15e8df8org.highwire.dtl.DTLVardef@baa5e5org.highwire.dtl.DTLVardef@1e181aaorg.highwire.dtl.DTLVardef@7c3f0_HPS_FORMAT_FIGEXP M_FIG C_FIG Novelty and ImpactOur work demonstrates that TP53 regulates transcriptionally SOX2 through binding to its promoter and the SRR2 enhancer. Increased expression of SOX2 promotes an EMT and increased migration. Breast cancer patients with genetic alteration of TP53 show increased levels of SOX2 and a more metastatic phenotype. This work is a key demonstration of an additional effect of genetic alterations of TP53, leading to de-repression of SOX2 and alteration of cancer cell plasticity with important phenotypic consequences.

cancer biology↗

bioRxiv2024

Loss of the Inv(16) Oncogene CBFB::MYH11 Eliminates Leukemia from the Blood and Spleen, but not the Bone Marrow

Inversion of chromosome 16 [inv(16)] generates the fusion gene CBFB::MYH11 (CM) and is one of the most common chromosomal rearrangements in Acute Myeloid Leukemia (AML). Expression of CM is required for leukemia initiation. Patients with inv(16) at diagnosis invariably have the rearrangement at relapse, leading to the assumption that CM is also required after leukemic transformation. However, a role for CM in leukemia maintenance has yet to be shown experimentally. To address this, we used an inducible CM knockdown (KD) mouse model and found that decreased CM eliminated leukemia cells from the peripheral blood and spleen, but not the bone marrow, despite all populations exhibiting significantly decreased CM mRNA and protein. The surviving CM KD cells in the bone marrow showed decreased apoptosis and proliferation, and increased expression of autophagy related genes. Surprisingly, with prolonged KD of CM, [~]40% of mice re-established disease despite maintaining decreased CM. Our work indicates that CM is required for leukemia survival in the spleen and peripheral blood, but in the bone marrow CM KD leukemia cells can survive and re-establish disease independent of the fusion protein. These findings imply that targeting CM alone has potential to reduce leukemic burden but not cure the disease.

cancer biology↗

bioRxiv2024

Illuminating microbial mat assembly: Cyanobacteria and Chloroflexota cooperate to structure light-responsive biofilms

Microbial mats are stratified communities often dominated by unicellular and filamentous phototrophs within an exopolymer matrix. It is challenging to quantify the dynamic responses of community members in situ as they experience steep gradients and rapid fluctuations of light. To address this, we developed a binary consortium using two representative isolates from hot spring mats: the unicellular oxygenic phototrophic cyanobacterium Synechococcus OS-B (Syn OS-B) and the filamentous anoxygenic phototroph Chloroflexus MS-CIW-1 (Chfl MS-1). We quantified the motility of individual cells and entire colonies and demonstrated that Chfl MS-1 formed bundles of filaments that moved in all directions with no directional bias to light. Syn OS- B was slightly less motile but exhibited positive phototaxis. This binary consortium displayed cooperative behavior by moving further than either species alone and formed ordered arrays where both species aligned with the light source. No cooperative motility was observed when a non-motile pilB mutant of Syn OS-B was used instead of Syn OS-B. The binary consortium also produced more adherent biofilm than individual species, consistent with the close interspecies association revealed by electron microscopy. We propose that cyanobacteria and Chloroflexota cooperate in forming natural microbial mats, by colonizing new niches and building robust biofilms. SignificanceMicrobial mats are dense, layered communities with ancient origins and widespread occurrence, but how they assemble is not well understood. To investigate how microbial motility, physical interactions, and responses to light affect mat assembly, we developed a binary consortium from representative hot spring mat isolates. Individually, the Cyanobacteria and Chloroflexota isolates displayed significant differences in motility and biofilm formation. When combined, the consortium exhibited enhanced motility towards light and formed more robust biofilms. This model consortium approach complements in situ studies by directly testing the role of motility and physical cooperation in shaping microbial mats, and could inform biofilm applications in industrial settings.

microbiology↗

bioRxiv2024

Cx43 Enhances Response to BRAF/MEK Inhibitors by Reducing DNA Repair Capacity

BRAF and MEK inhibitors (BRAF/MEKi) have radically changed the treatment landscape of advanced BRAF mutation-positive tumours. However, limited efficacy and emergence of drug resistance are major handicaps for successful treatments. Here, by using relevant preclinical models, we found that Connexin43 (Cx43), a protein that plays a role in cell-to-cell communication, increases effectiveness of BRAF/MEKi by recruiting DNA repair complexes to lamin-associated domains and promoting persistent DNA damage and cellular senescence. The nuclear compartmentalization promoted by Cx43 contributes to genome instability and synthetic lethality caused by excessive DNA damage, which could lead to a novel therapeutic approach for these tumours to overcome drug resistance. Based on these findings, we designed an innovative drug combination using small extracellular vesicles (sEVs) to deliver the full-Cx43 in combination with the BRAF/MEKi. This study reveals Cx43 as a new player on DNA repair and BRAF/MEKi response, underlining the therapeutical potential that this approach could eventually have in the clinic to overcome the limitations of current therapies and improve treatment outcomes for patients with advanced BRAF mutant tumours.

cancer biology↗

bioRxiv2021

B cells adapt their nuclear morphology to organize the immune synapse and help antigen extraction

Upon interaction with immobilized antigens B cells form an immune synapse, where actin remodeling and re-positioning of the microtubule-organizing center (MTOC) together with lysosomes can facilitate antigen extraction. B cells have restricted cytoplasmic space, mainly occupied by a large nucleus, yet the role of nuclear morphology in the formation of the immune synapse has not been addressed. Here we show that, upon activation, B cells re-orientate and adapt the size of their nuclear groove facing the immune synapse, where the MTOC sits and lysosomes accumulate. Silencing nuclear envelope proteins, Nesprin-1 and Sun-1, impairs nuclear reorientation towards the synapse and leads to defects in actin organization at this level. Consequently, B cells are unable to internalize the BCR after antigen activation. Nesprin-1 and Sun-1-silenced B cells also fail to accumulate the tethering factor Exo70 at the center of the synaptic membrane and display defective lysosome positioning, impairing efficient antigen extraction at the immune synapse. Thus, changes in nuclear morphology and positioning emerge as critical regulatory steps to coordinate B cell activation.

cell biology↗

bioRxiv2021

Aberrant integration of Hepatitis B virus DNA promotes major restructuring of human hepatocellular carcinoma genome architecture

Most cancers are characterized by the somatic acquisition of genomic rearrangements during tumour evolution that eventually drive the oncogenesis. There are different mutational mechanisms causing structural variation, some of which are specific to particular cancer types. Here, using multiplatform sequencing technologies, we identify and characterize a remarkable mutational mechanism in human hepatocellular carcinoma caused by Hepatitis B virus, by which DNA molecules from the virus are inserted into the tumour genome causing dramatic changes in its configuration, including non-homologous chromosomal fusions and megabase-size telomeric deletions. This aberrant mutational process, present in at least 8% of all HCC tumours, is active early during liver cancer evolution and can provide the driver rearrangements that a cancer clone requires to survive and grow.

cancer biology↗

bioRxiv2016

Highly-efficient Cpf1-mediated gene targeting in mice following high concentration pronuclear injection

Cpf1 has emerged as an alternative to the Cas9 RNA-guided nuclease. Here we show that gene targeting rates in mice using Cpf1 can meet or even surpass Cas9 targeting rates (approaching 100% targeting) but require higher concentrations of mRNA and guide. We also demonstrate that co-injecting two guides with close targeting sites can result in synergistic genomic cutting, even if one of the guides has minimal cutting activity.

genetics↗