CENTRO DE BIOLOGÍA MOLECULAR SEVERO OCHOACaptura de pantalla 2022 09 14 a las 10.27.10    

Representative publications

Ugo Bastolla, David Abia, Oscar Piette

Motivation: Evolutionary inference depends crucially on the quality of multiple sequence alignments (MSA), which is problematic for distantly re-lated proteins. Since protein structure is more conserved than sequence, it seems natural to use structure alignments for distant homologs. However, structure alignments may not be suitable for inferring evolutionary relationships.
Results: Here we examined four protein similarity measures that depend on sequence and structure (fraction of aligned residues, sequence identity, fraction of superimposed residues, and contact overlap), finding that they are intimately correlated but none of them provides a com-plete and unbiased picture of conservation in proteins. Therefore, we propose the new hybrid protein sequence and structure similarity score PC_sim based on their main principal component. The corresponding divergence measure PC_div shows the strongest correlation with divergen-ces obtained from individual similarities, suggesting that it infers accurate evolutionary divergences. We developed the program PC_ali that con-structs protein MSAs either de novo or modifying an input MSA, using a similarity matrix based on PC_sim. The program constructs a starting MSA based on the maximal cliques of the graph of these PAs and it refines it through progressive alignments along the tree reconstructed with PC_div. Compared with eight state-of-the-art multiple structure or sequence alignment tools, PC_ali achieves higher or equal aligned fraction and structural scores, sequence identity higher than structure aligners although lower than sequence aligners, highest score PC_sim, and highest similarity with the MSAs produced by other tools and with the reference MSA Balibase.
Availability and implementation: https://github.com/ugobas/PC_ali

Publication Date: 17 October 2023    https://doi.org/10.1093/bioinformatics/btad630

Lucia Alvaro-Aranda, Ambre Petitalot, Yasmina Djeghmoum, Davide Panig ada, Jenny Kaur Singh, Åsa Ehlén, Domagoj Vugic,Charlotte Martin, Simona Miron, Aida Contreras-Perez, Naima Nhiri, Virginie Boucherit, Philippe Lafitte, Isaac Dumoulin, Etienne Rouleau, Eric Jacquet, Lidia Feliubadaló, Jesús del Valle, Dominique Stoppa-Lyonnet, Sophie Zinn-Justin, Conxi Lázaro, Sandrine M. Caputo and Aura Carreira

BRCA2 tumor suppressor protein ensures genome integrity by mediating DNA repair via homologous recombination ( HR) . This function is e x ecuted in part by its canonical DNA binding domain located at the C-terminus ( BRCA2 CTD) , the only folded domain of the protein. Most germline pathogenic missense variants are located in this highly conserved region which binds to single-stranded DNA ( ssDNA) and to the acidic protein DSS1. These interactions are essential for the HR function of BRCA2. Here, we report that the variant R2645G, identified in breast cancer and located at the DSS1 interf ace, une xpectedly increases the ssDNA binding activity of BRCA2 CTD in vitro. Human cells expressing this variant displa y a h yper-recombination phenot ype, chromosomal inst abilit y in the form of chromatid gaps when exposed to DNA damage, and increased P ARP inhibitor sensitivity. In mouse embryonic stem cells ( mES) , this variant alters viability and confers sensitivity to cisplatin and Mitom y cin C. These results suggest that BRCA2 interaction with ssDNA needs to be tightly regulated to limit HR and prevent chromosomal inst abilit y and we propose that this control mechanism in v olv es DSS1. Giv en that se v eral missense v ariants located within this region ha v e been identified in breast cancer patients, these findings might ha v e clinical implications for carriers.

Accepted: December 12, 2023    https://doi.org/10.1093/nar/gkad1222

Carl P. Lehmann, Paula González-Fernández and José Antonio Tercero

The Rad5 / HLTF protein has a central role in the tolerance to DNA damage by mediating an error-free mode of bypassing unrepaired DNA lesions, and is therefore critical for the maintenance of genome st abilit y. We show in this w ork that, f ollo wing cellular stress, Rad5 is regulated by relocalization into t wo t ypes of nuclear foci that coexist within the same cell, which we termed ‘S’ and ‘I’. Rad5 S-f oci f orm in response to genotoxic stress and are associated with Rad5’s function in maintaining genome stability, whereas I-foci form in the presence of proteotoxic stress and are related to Rad5’s own proteostasis. Rad5 accumulates into S-foci at DNA damage tolerance sites by liquid-liquid phase separation, while I-foci constitute sites of chaperone-mediated sequestration of Rad5 at the intranuclear quality control compartment ( INQ) . Relocalization of Rad5 into each type of foci involves different pathways and recruitment mechanisms, but in both cases is driven by the evolutionarily conserved E2 ubiquitin-conjugating enzyme Rad6. This coordinated differential relocalization of Rad5 interconnects DNA damage response and proteostasis net works, highlighting the import ance of studying these homeost asis mechanisms in t andem. Spatial regulation of Rad5 under cellular stress conditions thus provides a useful biological model to study cellular homeostasis as a whole.

Published: 06 December 2023    https://doi.org/10.1093/nar/gkad1176

Natalia Colás-Algora, Pablo Muñoz-Pinillos, Cristina Cacho-Navas , José Avendaño-Ortiz , Gema de Rivas, Susana Barroso, Eduardo López-Collazo, Jaime Millán

Systemic inflammatory diseases, such as sepsis and severe COVID-19, provoke acute respiratory distress syndrome in which the pathological hyperpermeability of the microvasculature, induced by uncontrolled inflammatory stimulation, causes pulmonary edema. Identifying the inflammatory mediators that induce human lung microvascular endothelial cell barrier dysfunction is essential to find the best anti-inflammatory treatments for critically ill acute respiratory distress syndrome patients.

Key Words: endothelial cell  interleukin  interferon  permeability  respiratory distress syndrome sepsis

Published: 21 Sep 2023    https://doi.org/10.1161/ATVBAHA.123.319695

José M. Izquierdo

Wound healing is a coordinated process that can be divided into three general phases: inflammatory processes, tissue formation and tissue remodeling. The molecular and cellular events involved in healing, repair and regeneration are still poorly understood, and current therapies are limited. As a result, defective wound healing affects millions of people worldwide every year. Beyond the current wound healing dogma, new mediators and regulatory nodes are continuously being discovered, opening new therapeutic avenues.

Key Words: mTORC1, de novo translation, wound healing, repair, regeneration, regenerative medicine

Accepted:  2023    https://doi-org/10.3389/fcell.2023.1294934

Tamara Rosell-Garcia, Sergio Rivas-Muñoz, Koryu Kin, Verónica Romero-Albillo, Silvia Alcaraz, Carlos Fernandez-Tornero, Fernando Rodriguez-Pascual

Transcriptional activity of the hypoxia inducible factor (HIF) relies on the formation of a heterodimer composed of an oxygen-regulated α-subunit and a stably expressed β-subunit. Heterodimeric HIF activates expression by binding to RCGTG motifs within promoters of hypoxia-activated genes. Some hypoxia targets also possess an adjacent HIF ancillary sequence (HAS) reported to increase transcription but whose function remains obscure. Here, we investigate the contribution of the HAS element to the hypoxia response and its mechanism of action, using the HAS-containing prolyl 4-hydroxylase subunit α1 (P4HA1) as a gene model in NIH/3T3 mouse em-bryonic fibroblasts and HEK293 human embryonic kidney cells. Our HIF overexpression experiments demon-strate that the HAS motif is essential for full induction by hypoxia and that the presence of the tandem HAS/HIF, as opposed to HIF-only sequences, provides HIF proteins with the capacity to form complexes of stoichiometry beyond the classical heterodimer, likely tetramers, to cooperatively potentiate hypoxia-induced transcription. We also provide evidence of the crucial role played by the Fα helix of the PAS-B domain of the HIF1β subunit to support the interaction between heterodimers. Functional analysis showed that human genes containing the HAS/HIF motifs are better responders to hypoxia, and their promoters are enriched for specific transcription factor binding sites. Gene ontology enrichment revealed a predominance of HAS/HIF in genes primarily related to tissue formation and development. Our findings add an extra level of regulation of the hypoxia/HIF signaling through multimerization of HIF proteins on regulatory elements containing the HAS/HIF motifs.  

Key Words: Hypoxia inducible factor, Hypoxia response, Cooperation, HIF ancillary sequence, HIF binding site

Available online 25 July 2023    https://doi.org/10.1016/j.bbagrm.2023.194963

Esperanza López‑Merino, María I. Cuartero, José A. Esteban, Víctor Briz

Increasing evidence from animal and epi-demiological studies indicates that perinatal exposure to pesticides cause developmental neurotoxicity and may increase the risk for psychiatric disorders such as autism and intellectual disability. However, the under-lying pathogenic mechanisms remain largely elusive. This work was aimed at testing the hypothesis that developmental exposure to different classes of pesti-cides hijacks intracellular neuronal signaling contrib-uting to synaptic and behavioral alterations associ-ated with neurodevelopmental disorders (NDD). Low concentrations of organochlorine (dieldrin, endosul-fan, and chlordane) and organophosphate (chlorpyri-fos and its oxon metabolite) pesticides were chroni-cally dosed ex  vivo (organotypic rat hippocampal slices) or in  vivo (perinatal exposure in rats), and then biochemical, electrophysiological, behavioral, and protzeomic studies were performed. All the pes-ticides tested caused prolonged activation of MAPK/ERK pathway in a concentration-dependent manner. Additionally, some of them impaired metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD). In the case of the pesticide chlor-dane, the effect was attributed to chronic modulation of MAPK/ERK signaling. These synaptic alterations were reproduced following developmental in  vivo exposure to chlordane and chlorpyrifos-oxon, and were also associated with prototypical behavioral phenotypes of NDD, including impaired motor devel-opment, increased anxiety, and social and memory deficits. Lastly, proteomic analysis revealed that these pesticides differentially regulate the expres-sion of proteins in the hippocampus with pivotal roles in brain development and synaptic signaling, some of which are associated with NDD. Based on these results, we propose a novel mechanism of syn-aptic dysfunction, involving chronic overactivation of MAPK and impaired mGluR-LTD, shared by differ-ent pesticides which may have important implications for NDD.

Key Words:  Contaminants · Kinase signaling · Psychiatric disorders · Neurodevelopment · MAPK · mGluR LTD

Published: 08 February 2022    https://doi.org/10.1007/s10565-022-09697-2

Verónica Miguel, Carlos Rey-Serra, Jessica Tituaña, Belén Sirera, Elena Alcalde-Estévez, Ignacio Herrero, Irene Ranz, Laura Fernández, Carolina Castillo, Lucía Sevilla, James Nagai, Katharina C. Reimer, Jitske Jansen, Rafael Kramann, Ivan G. Costa, Ana Castro, David Sancho, José Miguel Rodríguez González-Moro, Santiago Lamas

Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. It is the final outcome of the acute respiratory distress syndrome (ARDS), characterized by an initial exacerbated inflammatory response, metabolic derangement and ultimate tissue scarring. A positive balance of cellular energy may result crucial for the recovery of clinical COVID-19. Hence, we asked if two key pathways involved in cellular energy generation, AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling and fatty acid oxidation (FAO) could be beneficial. We tested the drugs metformin (AMPK activator) and baicalin (CPT1A activator) in different experimental models mimicking COVID-19 associated inflammation in lung and kidney. We also studied two different cohorts of COVID-19 patients that had been previously treated with metformin. These drugs ameliorated lung damage in an ARDS animal model, while activation of AMPK/ ACC signaling increased mitochondrial function and decreased TGF-β-induced fibrosis, apoptosis and inflam- mation markers in lung epithelial cells. Similar results were observed with two indole derivatives, IND6 and IND8 with AMPK activating capacity. Consistently, a reduced time of hospitalization and need of intensive care was observed in COVID-19 patients previously exposed to metformin. Baicalin also mitigated the activation of pro-inflammatory bone marrow-derived macrophages (BMDMs) and reduced kidney fibrosis in two animal models of kidney injury, another key target of COVID-19. In human epithelial lung and kidney cells, both drugs improved mitochondrial function and prevented TGF-β-induced renal epithelial cell dedifferentiation. Our results support that favoring cellular energy production through enhanced FAO may prove useful in the prevention of COVID-19-induced lung and renal damage.

Accepted 1 November 2023   https://doi.org/10.1016/j.redox.2023.102957

Marta García-Juan, Lara Ordóñez-Gutiérrez, Francisco Wandosell

Proteostasis mechanisms mediated by macroautophagy/autophagy are altered in neurodegenerative diseases such as Alzheimer disease (AD) and their recovery/enhancement has been proposed as a therapeutic approach. From the two central nodes in the anabolism–catabolism balance, it is generally accepted that mechanistic target of rapamycin kinase complex 1 (MTORC1)_ activation leads to the inhibition of autophagy, whereas adenosine 50-monophosphate (AMP)-activated protein kinase (AMPK) has the opposite role. In AD, amyloid beta (Aβ) production disturbs the optimal neuronal/glial proteostasis. As astrocytes are essential for brain homeostasis, the purpose of this work was to analyze if the upregulation of autophagy in this cell type, either by MTORC1 inhibition or AMPK activation, could modulate the generation/degradation of β-amyloid. By using primary astrocytes from amyloid beta precursor protein (APP)/Presenilin 1 (PSEN1) mouse model of AD, we confirmed that MTORC1 inhibition reduced Aβ secretion through moderate autophagy induction. Surprisingly, pharmacologically increased activity of AMPK did not enhance autophagy but had different effects on Aβ secretion. Conversely, AMPK inhibition did not affect autop-hagy but reduced Aβ secretion. These puzzling data were confirmed through the overexpression of different mutant AMPK isoforms: while only the constitutively active AMPK increased autophagy, all versions augmented Aβ secretion. We con-clude that AMPK has a significantly different role in primary astrocytes than in other reported cells, similar to our previous findings in neurons. Our data support that per-haps only a basal AMPK activity is needed to maintain autophagy whereas the increased activity, either physiologically or pharmacologically, has no direct effect on autophagy-dependent amyloidosis. These results shed light on the controversy about the therapeutic effect of AMPK activation on autophagy induction.

Key Words:  AICAR, Alzheimer, amyloid accumulation, autophagy, cultured astrocytes, metformin, rapamycin

Published: 27 November 2023    https://doi.org/10.1002/glia.24492

Marta Lacuna, Alejandro M. Hortal, Claudia Cifuentes, Tania Gonzalo, Miguel Alcoceba, Miguel Bastos, Xosé R. Bustelo, Marcos González and Balbino Alarcón

Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by progres-sive accumulation of a rare population of CD5+ B-lymphocytes in peripheral blood, bone marrow, and lymphoid tissues. CLL exhibits remarkable clinical heterogeneity, with some patients presenting with indolent disease and others progressing rapidly to aggressive CLL. The significant heterogeneity of CLL underscores the importance of identifying novel prognostic markers. Recently, the RAS-related gene RRAS2 has emerged as both a driver oncogene and a potential marker for CLL progression, with higher RRAS2 expression associated with poorer disease prognosis. Although missense somatic mutations in the coding sequence of RRAS2 have not been described in CLL, this study reports the frequent detection of three somatic mutations in the 3´ untranslated region (3´UTR) affecting positions+26, +53, and +180 downstream of the stop codon in the mRNA. An inverse relationship was observed between these three somatic mutations and RRAS2 mRNA expression, which correlated with lower blood lymphocytosis. These findings highlight the importance of RRAS2 overexpression in CLL development and prognosis and point to somatic mutations in its 3´UTR as novel mechanistic clues. Our results may contribute to the development of targeted therapeutic strategies and improved risk stratification for CLL patients.

Key Words: RRAS2; somatic mutations; 3´ untranslated region; Chronic Lymphocytic Leukemia (CLL); clinical implications

Published: 22 November 2023    https://doi.org/10.3390/cells12232687

Abrusci Concepción, Amils Ricardo and Sánchez-León Enrique

A specific microorganism, Pantoea agglomerans uam8, was isolated from the ionic liquid (IL) Choline NTF2 and identified by molecular biology. A biodegradation study was performed at osmolarity conditions (0.2, 0.6, 1.0 M). These had an important influence on the growth of the strain, exopolysaccharide (EPS) production, and biodegradation (1303 mg/L max production and 80% biodegradation at 0.6 M). These conditions also had an important influence on the morphology of the strain and its EPSs, but not in the chemical composition. The EPS (glucose, mannose and galactose (6:0.5:2)) produced at 0.6 M was further characterized using different techniques. The obtained EPSs presented important differences in the behavior of the emulsifying activity for vegetable oils (olive (86%), sunflower (56%) and coconut (90%)) and hydrocarbons (diesel (62%), hexane (60%)), and were compared with commercial emulsifiers. The EPS produced at 0.6 M had the highest emulsifying activity overall. This EPS did not show cytotoxicity against the tested cell line (<20%) and presented great advantages as an antioxidant (1,1-diphenyl-2-picryl-hydrazyl radical (DPPH) (85%), hydroxyl radical (OH) (99%), superoxide anion (O2) (94%), chelator (54%), and antimicrobial product (15 mm). The osmolarity conditions directly affected the capacity of the strain to biodegrade IL and the subsequently produced EPS. Furthermore, the EPS produced at 0.6 M has potential for environmental applications, such as the removal of hazardous materials by emulsification, whilst resulting in positive health effects such as antioxidant activity and non-toxicity.

Keywords:  bacteria; ionic liquid; toxicity; emulsifying; antioxidant

Published: 3 October 2023    https://doi.org/10.3390/polym15193974

Alejandro Valbuena, Klara Strobl, Juan Carlos Gil-Redondo, Luis Valiente, Pedro J. de Pablo, Mauricio G. Mateu

Infection of humans by many viruses is typically initiated by the internalization of a single virion in each of a few susceptible cells. Thus, the outcome of the infection process may depend on stochastic single-molecule events. A crucial process for viral infection, and thus a target for developing antiviral drugs, is the uncoating of the viral genome. Here a force spectroscopy procedure using an atomic force microscope is implemented to study uncoating for individual human rhinovirus particles. Application of an increasing mechanical force on a virion led to a high force-induced structural transition that facilitated extrusion of the viral RNA molecule without loss of capsid integrity. Application of force to virions that h ad previously extruded the RNA, or to RNA-free capsids, led to a lower force-induced event associated with capsid disruption. The kinetic parameters are determined for each reaction. The high-force event is a stochastic process governed by a moderate free energy barrier (≈20 kcal mol−1), which results in a heterogeneous population of structurally weakened virions in which different fractions of the RNA molecule are externalized. The effects of antiviral compounds or capsid mutation on the kinetics of this reaction reveal a correlation between the reaction rate and virus infectivity.

Published: 08 October 2023    https://doi.org/10.1002/smll.202304722

Francesc Muyas, Manuel José Gómez Rodriguez, Rita Cascão, Angela Afonso, Carolin M. Sauer, Claudia C. Faria, Isidro Cortés-Ciriano & Ignacio Flores

Telomere fusions (TFs) can trigger the accumulation of oncogenic alterations leading to malignant transformation and drug resistance. Despite their relevance in tumour evolution, our understanding of the patterns and consequences of TFs in human cancers remains limited. Here, we characterize the rates and spectrum of somatic TFs across >30 cancer types using whole-genome sequencing data. TFs are pervasive in human tumours with rates varying markedly across and within cancer types. In addition to end-to-end fusions, we find patterns of TFs that we mechanistically link to the activity of the alternative lengthening of telomeres (ALT) pathway. We show that TFs can be detected in the blood of cancer patients, which enables cancer detection with high specificity and sensitivity even for early-stage tumours and cancers of high unmet clinical need. Overall, we report a genomic footprint that enables characterization of the telomere maintenance mechanism of tumours and liquid biopsy analysis.

Published:    https://doi.org/10.1038/s41467-023-44287-8

A. Contreras; C. Perea-Resa

Transcription represents a central aspect of gene expression with RNA polymerase machineries (RNA Pol) driving the synthesis of RNA from DNA template molecules. In eukaryotes, a total of three RNA Pol enzymes generate the plethora of RNA species and RNA Pol II is the one transcribing all protein-coding genes. A high number of cis- and trans-acting factors orchestrates RNA Pol II-mediated transcription by influencing the chromatin recruitment, activation, elongation, and/or termination steps. The levels of DNA accessibility, defining open-euchromatin versus close-heterochromatin, delimits RNA Pol II activity as well as the encounter with other factors acting on chromatin such as the DNA replication or DNA repair machineries. The stage of the cell cycle highly influences RNA Pol II activity with mitosis representing the major challenge. In fact, there is a massive inhibition of transcription during the mitotic entry coupled with chromatin dissociation of most of the components of the transcriptional machinery. Mitosis, as a consequence, highly compromises the transcriptional memory and the perpetuation of cellular identity. Once mitosis ends, transcription levels immediately recover to define the cell fate and to safeguard the proper progression of daughter cells through the cell cycle. In this review, we evaluate our current understanding of the transcriptional repression associated with mitosis with a special focus on the molecular mechanisms involved, on the potential function behind the general repression, and on the transmission of the transcriptional machinery into the daughter cells. We finally discuss the contribution that errors in the inheritance of the transcriptional machinery across mitosis might play in stem cell aging.

Published; February 19 2024    https://doi.org/10.1042/BST20231071

EIván Ventoso, Juan José Berlanga, René Toribio and Irene Díaz-López

Alphaviruses can replicate in arthropods and in many vertebrate species including humankind, but only in vertebrate cells do infections with these viruses result in a strong inhibition of host translation and transcription. Translation shutoff by alphaviruses is a multifactorial process that involves both host- and virus-induced mechanisms, and some of them are not completely understood. Alphavirus genomes contain cis-acting elements (RNA structures and dinucleotide composition) and encode protein activities that promote the translational and transcriptional resistance to type I IFN-induced antiviral effectors. Among them, IFIT1, ZAP and PKR have played a relevant role in alphavirus evolution, since they have promoted the emergence of multiple viral evasion mechanisms at the translational level. In this review, we will discuss how the adaptations of alphaviruses to vertebrate hosts likely involved the acquisition of new features in viral mRNAs and proteins to overcome the effect of type I IFN.

Keywords:
alphaviruses; translation initiation; eIF2α phosphorylation; RNA structure; antiviral response; interferon; evolution; host range

Published: 30 January 2024    https://doi.org/10.3390/v16020205

Antonio Lahera, Laura Vela-Martín, Pablo Fernández-Navarro, Pilar Llamas, José L. López-Lorenzo, Javier Cornago, Javier Santos, José Fernández-Piqueras, María Villa-Morales

T-cell acute lymphoblastic leukemia (T-ALL) arises from the malignant transformation of T-cell progenitors at various differentiation stages. Given that patients who relapse have a dismal prognosis, there is an urgent need to identify the molecular alterations that are present in such patients and promote leukemogenesis to implement personalized therapies with higher efficacy and fewer adverse effects. In the present manuscript, we identified the JAK3Q988P mutation in a T-ALL patient who did not achieve a durable response after the conventional treatment and whose tumor cells at relapse presented constitutive activation of the JAK/STAT pathway. Although JAK3Q988P has been previously identified in T-ALL patients from different studies, the functional consequences exerted by this mutation remain unexplored. Through the combination of different hematopoietic cellular models, we functionally characterize JAK3Q988P as an oncogenic mutation that contributes to leukemogenesis. Notably, JAK3Q988P not only promotes constitutive activation of the JAK/STAT pathway in the absence of cytokines and growth factors, as is the case for other JAK3 mutations that have been functionally characterized as oncogenic, but also functions independently of JAK1 and IL2RG, resulting in high oncogenic potential as well as resistance to ruxolitinib. Our results indicate that ruxolitinib may not be efficient for future patients bearing the JAK3Q988P mutation who instead may obtain greater benefits from treatments involving other pharmacological inhibitors such as tofacitinib.

First published: 15 September 2023   https://doi.org/10.1002/mc.23632
María Jesús Ruiz-Rodríguez Jorge Oller, Sara Martínez-Martínez, Iván Alarcón-Ruiz , Marta Toral, Yilin Sun, Ángel Colmenar, María José Méndez-Olivares, Dolores López-Maderuelo, Christine B Kern, J Francisco Nistal, Arturo Evangelista, Gisela Teixido-Tura, Miguel R Campanero, and Juan Miguel Redondo

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations. While various conditions causing TAAD exhibit aortic accumulation of the proteoglycans versican (Vcan) and aggrecan (Acan), it is unclear whether these ECM proteins are involved in aortic disease. Here, we find that Vcan, but not Acan, accumulated in Fbn1C1041G/+ aortas, a mouse model of MFS. Vcan haploinsufficiency protected MFS mice against aortic dilation, and its silencing reverted aortic disease by reducing Nos2 protein expression. Our results suggest that Acan is not an essential contributor to MFS aortopathy. We further demonstrate that Vcan triggers Akt activation and that pharmacological Akt pathway inhibition rapidly regresses aortic dilation and Nos2 expression in MFS mice. Analysis of aortic tissue from MFS human patients revealed accumulation of VCAN and elevated pAKT-S473 staining. Together, these findings reveal that Vcan plays a causative role in MFS aortic disease in vivo by inducing Nos2 via Akt activation and identify Akt signaling pathway components as candidate therapeutic targets.

Published on line: 2 January 2024    https://doi.org/10.1038/s44321-023-00009-7

 
José M. Izquierdo 

In their recent Science article, Singh et al. identified taurine as an endogenously produced anti-inflammatory, anti-immunosenescence, and anti-aging molecule. The authors also show that restoring taurine to its “youthful” levels prevents inflammation, boosts the immune response, and delays inflammaging/aging.

Published on line:     https://www.doi.org/10.1038/s41423-023-01062-5

 
Cristina M. Ostalé, Alicia del Prado, Mercedes Martín, Nuria Esteban, Ana López-Varea, Jose F. de Celis

The Spalt transcriptional regulators participate in a variety of cell fate decisions during multicellular development. Vertebrate Spalt proteins have been mostly associated to the organization of heterochromatic regions, but they also contribute regulatory functions through binding to A/T rich motives present in their target genes. The developmental processes in which the Drosophila spalt genes participate are well known through genetic analysis, but the mechanism by which the Spalt proteins regulate transcription are still unknown. Furthermore, despite the prominent changes in gene expression associated to mutations in the spalt genes, the specific DNA sequences they bind are unknow. Here, we analyze a DNA fragment present in the regulatory region of the knirps gene. Spalt proteins are candidate repressors of knirps expression during the formation of the venation pattern in the wing disc, and we identified a minimal conserved 30bp sequence that binds to Spalt major both in vivo and in vitro. This sequence mediates transcriptional repression in the central region of the wing blade, constituting the first confirmed case of a direct regulatory interaction between Spalt major and its target DNA in Drosophila. Interestingly, we also find similar sequences in a set of eight novel candidate Spalt target genes, pointing to a common mechanism of transcriptional repression mediated by Spalt proteins.

Volume 510, June 2024, Pages 40-49    https://doi.org/10.1016/j.ydbio.2024.03.004

 
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Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations. While various conditions causing TAAD exhibit aortic accumulation of the proteoglycans versican (Vcan) and aggrecan (Acan), it is unclear whether these ECM proteins are involved in aortic disease. Here, we find that Vcan, but not Acan, accumulated in Fbn1C1041G/+ aortas, a mouse model of MFS. Vcan haploinsufficiency protected MFS mice against aortic dilation, and its silencing reverted aortic disease by reducing Nos2 protein expression. Our results suggest that Acan is not an essential contributor to MFS aortopathy. We further demonstrate that Vcan triggers Akt activation and that pharmacological Akt pathway inhibition rapidly regresses aortic dilation and Nos2 expression in MFS mice. Analysis of aortic tissue from MFS human patients revealed accumulation of VCAN and elevated pAKT-S473 staining. Together, these findings reveal that Vcan plays a causative role in MFS aortic disease in vivo by inducing Nos2 via Akt activation and identify Akt signaling pathway components as candidate therapeutic targets.

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Published on line: 2 January 2024    https://doi.org/10.1038/s44321-023-00009-7

 
María Jesús Ruiz-Rodríguez Jorge Oller, Sara Martínez-Martínez, Iván Alarcón-Ruiz , Marta Toral, Yilin Sun, Ángel Colmenar, María José Méndez-Olivares, Dolores López-Maderuelo, Christine B Kern, J Francisco Nistal, Arturo Evangelista, Gisela Teixido-Tura, Miguel R Campanero, and Juan Miguel Redondo

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations. While various conditions causing TAAD exhibit aortic accumulation of the proteoglycans versican (Vcan) and aggrecan (Acan), it is unclear whether these ECM proteins are involved in aortic disease. Here, we find that Vcan, but not Acan, accumulated in Fbn1C1041G/+ aortas, a mouse model of MFS. Vcan haploinsufficiency protected MFS mice against aortic dilation, and its silencing reverted aortic disease by reducing Nos2 protein expression. Our results suggest that Acan is not an essential contributor to MFS aortopathy. We further demonstrate that Vcan triggers Akt activation and that pharmacological Akt pathway inhibition rapidly regresses aortic dilation and Nos2 expression in MFS mice. Analysis of aortic tissue from MFS human patients revealed accumulation of VCAN and elevated pAKT-S473 staining. Together, these findings reveal that Vcan plays a causative role in MFS aortic disease in vivo by inducing Nos2 via Akt activation and identify Akt signaling pathway components as candidate therapeutic targets.

Published on line: 2 January 2024    https://doi.org/10.1038/s44321-023-00009-7

 

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    • Personalization cookies: those that allow the user to access the service with some predefined general characteristics based on a series of criteria in the user's terminal, such as the language, the type of browser through which the user accesses the service, the regional configuration from where you access the service, etc.
    • Analytical cookies: those that allow the person responsible for them to monitor and analyse the behaviour of the users of the websites to which they are linked. The information collected through this type of cookies is used in the measurement of the activity of the websites, applications or platforms, and for the elaboration of navigation profiles of the users of said sites, applications and platforms, in order to introduce improvements in the analysis of the data of use made by the users of the service.

Cookies used on our website

The CBMSO website uses Google Analytics. Google Analytics is a simple and easy to use tool that helps website owners to measure how users interact with the content of the site. You can consult more information about the cookies used by Google Analitycs in this link.

Acceptance of the Cookies Policy

The CBMSO assumes that you accept the use of cookies if you continue browsing, considering that it is a conscious and positive action from which the user's consent is inferred. In this regard, you are previously informed that such behaviour will be interpreted that you accept the installation and use of cookies.

Knowing this information, it is possible to carry out the following actions:

  • Accept cookies: if the user presses the acceptance button, this warning will not be displayed again when accessing any page of the portal.
  • Review the cookies policy: the user can access to this page in which the use of cookies is detailed, as well as links to modify the browser settings.

How to modify the configuration of cookies

Using your browser you can restrict, block or delete cookies from any web page. In each browser the process is different, here we show you links on this particular of the most used browsers:

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