Articles publicats en revistes (Genètica, Microbiologia i Estadística)

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The BMP pathway is essential for re-specification and maintenance of the dorsoventral axis in regenerating and intact planarians
(Elsevier, 2007) Molina Jiménez, M. Dolores; Saló i Boix, Emili; Cebrià Sánchez, Francesc
The bone morphogenetic protein (BMP) pathway has been shown to play an important role in the establishment of the dorsoventral axis during development in both vertebrate and invertebrate species. In an attempt to unravel the role of BMPs in pattern formation during planarian regeneration, we studied this signaling pathway in Schmidtea mediterranea. Here, we functionally characterize planarian homologues of two key elements of the pathway: Smed-BMP and Smed-Smad1. Whole-mount in situ hybridization showed that Smed-BMP is expressed at the planarian dorsal midline, suggesting a role in dorsoventral patterning, while Smed-Smad1 is widely expressed throughout the mesenchyme and in the central nervous system. RNA interference (RNAi) knockdowns of Smed-BMP or Smed-Smad1 led to the disappearance of dorsal markers along with the ectopic expression of ventral markers on the dorsal side of the treated animals. In almost all cases, a duplicated central nervous system differentiated dorsally after Smed-BMP or Smed-Smad1 RNAi. These defects were observed not only during regeneration but also in intact non-regenerating animals. Our results suggest that the BMP signaling pathway is conserved in planarians and that it plays a key role in the regeneration and maintenance of the dorsoventral axis.
Noggin and noggin-like genes control dorsoventral axis regeneration in planarians
(Elsevier, 2011) Molina Jiménez, M. Dolores; Neto, Ana; Maeso, Ignacio; Gómez-Skarmeta, José Luis; Saló i Boix, Emili; Cebrià Sánchez, Francesc
Planarians regenerate a whole animal from a small body piece within a few days. Recent studies have shown that the bone morphogenetic protein (BMP) pathway is required to reestablish the dorsoventral (DV) axis. In vertebrates, the specification of the DV axis depends on the coordinated action of a dual organizer defined by BMP and antidorsalizing morphogenetic protein (ADMP) under the control of several factors, including the inhibitors chordin and noggin. Planarians have an expanded noggin family (up to ten members), which have been classified as canonical noggin (nog) and noggin-like (nlg) genes, the latter carrying an insertion within the noggin domain. Here we show that a BMP/ADMP organizer governs DV axis reestablishment during planarian regeneration, highlighting a greater-than-thought conservation of the mechanisms that establish this axis in protostomes and deuterostomes. Also, we report that whereas noggin genes function as canonical BMP inhibitors, the silencing of planarian nlg induces ectopic neurogenesis and enhances ventralizing bmp(RNAi) phenotypes. Finally, we show that noggin-like genes are conserved from cnidarian to vertebrates and that both planarian nlg8 and Xenopus nlg ventralize Xenopus embryos when overexpressed. Remarkably, this ventralization is not associated with an increase in SMAD phosphorylation.
Role of the AmvAR efflux system on the pathogenesis of Acinetobacter baumannii
(Nature Publishing Group, 2026-12-01) Gaona, Marc; Corral, Jordi; Sánchez-Osuna, Miquel; Millán-Román, Carla; Balsalobre Parra, Carlos; Campoy, Susana; Barbé, Jordi; Aranda, Jesús; Pérez-Varela, María
extrusion is a key mechanism by which efflux pumps enable nosocomial pathogens to withstand exposure to antimicrobial compounds. In Acinetobacter baumannii, the AmvA efflux pump, belonging to the Major Facilitator Superfamily (MFS) and regulated by the TetR-family repressor AmvR, reduces susceptibility to disinfectants. Here, we investigated the broader functions of the AmvAR system beyond antimicrobial efflux. Our findings demonstrate that, in addition to conferring reduced susceptibility to disinfectants, the AmvAR system regulates the expression of cell surface components linked to pathogenic traits. Specifically, the A. baumannii AmvAR system contributes to motility and cell adhesion, thereby influencing biofilm formation. Loss of either the AmvA efflux pump or its transcriptional regulator AmvR significantly reduced biofilm development. Furthermore, disruption of regulatory control within this system led to a significant upregulation of the csuA pilus gene. Collectively, these results highlight the role of the AmvAR system in the pathogenesis of A. baumannii, underscoring its potential as a therapeutic target.
Genotype-phenotype correlations and putative modifier genes in SYNGAP1 encephalopathy
(Elsevier, 2026-03-17) Aranda, Selena; Ribeiro-Constante, Juliana; Tristán Noguero, Alba; Moreno-Ruiz, Nerea; Arenas Solà, Concepción; Martínez Calvo, Fernando Francisco; Ibañez-Micó, Salvador; Peña Segura, José Luis; Ramos-Fernández, José Miguel; Moyano Chicano, María del Carmen; Camino León, Rafael; Soto Insuga, Víctor; González-Alguacil, Elena; Dávila, Carlos Valera; Fernández-Jaén, Alberto; Plans, Laura; Camacho, Ana; Visa-Reñé, Nuria; Martin-Tamayo Blázquez, María del Pilar; Paredes-Carmona, Fernando; Marti-Carrera, Itxaso; Ginot-Julià, Guillem; Hernández-Fabián, Aránzazu; Tomàs Daví, Meritxell; Casadesús Sànchez, Mercè; Cuesta Herraiz, Laura; Fuentes Pita, Patricia; Bermejo Gonzalez, Teresa; O'Callaghan, Mar; Iglesias Santa Polonia, Federico Felipe; Rosario Cazorla, María; Lucas M.T.F.; González-Meneses, Antonio; Sala-Coromina, Júlia; Macaya Ruiz, Alfons; Lasa-Aranzasti, Amaia; Cueto-González, Ana María; Valera Párraga, Francisca; Campistol Plana, Jaume; Serrano, Mònica (Serrano Gutiérrez); Alonso Curcó, Xènia; Valenzuela Palafoll, Maria Irene; Monteagudo, Eines; Alonso-Colmenero, Itziar; Sans Capdevila, Oscar; Casals López, Ferran; Cormand Rifà, Bru; García Cazorla, Àngels; Bayés, Àlex; Mitjans Niubó, Marina
Synaptic Ras GTPase-Activating Protein 1 (SynGAP) is a key regulator of synaptic plasticity, neurodevelopment, and neuronal circuit function. It is encoded by the SYNGAP1 gene, in which de novo dominant pathogenic variants are a major cause of SYNGAP1 Encephalopathy, a rare neurodevelopmental disorder characterised by intellectual disability, epilepsy, autistic traits, and other clinical manifestations. While some genetic studies have reported genotype-phenotype correlations in this condition, our understanding of how specific genetic variants contribute to the heterogeneous clinical symptoms remain limited. Here, we analysed a cohort of 44 cases extensively characterised at the phenotypic level to investigate the impact of genetic variants in SYNGAP1 and in potentially modulatory genes on the clinical features of SYNGAP1 Encephalopathy. Our results include the identification of four previously unreported likely pathogenic SYNGAP1 variants associated with the disease. In our cohort, individuals carrying variants within the PH domain of SynGAP exhibit milder phenotypes compared with other patients. Finally, patients harbouring rare or low-frequency variants in SYNGAP1-related genes tend to present with higher global severity. Taken together, these findings suggest that the location of SYNGAP1 variants, together with additional genetic modifiers, may contribute to variability in clinical presentation and disease severity. Further studies in larger cohorts and functional validation are needed to refine genotype-phenotype correlations and to support the development of personalized management strategies.
GANs and artificial facial expressions in synthetic portraits
(MDPI, 2021-10-29) Rosado, Pilar; Fernández, Rubén; Reverter Comes, Ferran
Generative Adversarial Networks (GANs) provide powerful architectures for deep generative learning. GANs have enabled us to achieve an unprecedented degree of realism in the creation of synthetic images of human faces, landscapes, buildings, among others. Not only image generation, but also image manipulation is possible with GANs. Generative deep learning models are inherently limited in their creative abilities because of a focus on learning for perfection. We investigated the potential of GAN's latent spaces to encode human expressions, highlighting creative interest for suboptimal solutions rather than perfect reproductions, in pursuit of the artistic concept. We have trained Deep Convolutional GAN (DCGAN) and StyleGAN using a collection of portraits of detained persons, portraits of dead people who died of violent causes and people whose portraits were taken during an orgasm. We present results which diverge from standard usage of GANs with the specific intention of producing portraits that may assist us in the representation and recognition of otherness in contemporary identity construction.
Association of germline variants with KRAS-mutation status in colorectal cancer
(Nature Publishing Group, 2026-02-13) Tjader, Nijole Pollock; Ramroop, Johnny; Gandhi, Tanish; Dauch, Cara; Meadows, Owen; Stevens, Patrick; Pearlman, Rachel; Hampel, Heather; Aglago, Elom K.; Berndt, Sonja I.; Bloomer, Amanda; Brenner, Hermann; Buchanan, Daniel D; Campbell, Peter T.; Cao, Yin; Chan, Andrew T.; Cheng, Iona; Dimou, Niki; Drew, David A.; French, Amy J.; Georgeson, Peter; Giannakis, Marios; Giles, Graham G.; Gomez, Maria; Gruber, Stephen B.; Hoffmeister, Michael; Huang, Wen-Yi; Hullar, Meredith Aj.; Huyghe, Jeroen R.; Loroña, Nicole; Moreno Aguado, Víctor; Newton, Christina C.; Nowak, Jonathan A.; Obón Santacana, Mireia; Ogino, Shuji; Pellatt, Andrew J.; Peoples, Anita R.; Permuth, Jennifer B.; Schmit, Stephanie L.; Schoen, Robert E.; Siegel, Erin M.; Steinfelder, Robert; Sun, Wei; Teer, Jamie K.; Thomas, Claire E.; Trinh, Quang M.; Tsilidis, Konstantinos K.; Ugai, Tomotaka; Um, Caroline Y.; Van Guelpen, Bethany; Zaidi, Syed H.; Figueiredo, Jane C.; Peters, Ulrike; Phipps, Amanda I.; McElroy, Joseph Paul; Toland, Amanda E.
Somatic mutations in KRAS are a common driver of colorectal cancer (CRC) and present at different frequencies by race, sex, tumor site, ethnicity, and genetic similarity. Inherited germline variants may influence tumor somatic mutation frequency by altering mutation or DNA repair processes or altering cellular, immunological and/or microenvironmental responses after a mutation. We hypothesized that the germline genetic background modifies somatic KRAS mutation frequency in CRC. To test this, we performed a genome-wide association study (GWAS) in 7071 individuals with CRC, using KRAS mutation status as the phenotype. Single-nucleotide variants were chosen for validation analyses based on P values from the discovery GWAS, predicted in silico functional effects, and proximity to genes with potential cancer relevance. A validation analysis of 101 SNVs of interest was performed in 2482 individuals. No SNVs were significantly associated with KRAS-mutant CRC (P value < 0.0005). One variant rs73067863-T showed a non-significant exploratory association with fewer KRAS-mutant tumors in the combined sample (P value = 9.7 × 10–7, OR = 0.75). Follow-up studies are needed to determine if these or other germline variants impact population differences in KRAS mutations in CRC.
Experimental recombining of repetitive motifs leads to large functional metallothioneins and demonstrates their modular evolvability potential.
(Wiley, 2024-12-14) Dallinger, Reinhard; Pedrini-Martha, Veronika; Burdisso, María Lucía; Capdevila, Mercè; Palacios Bonilla, Òscar; Albalat Rodríguez, Ricard
Protein modularity is acknowledged for promoting the emergence of new protein variants via domain rearrangements. Metallothioneins (MTs) offer an excellent model system for experimentally examining the consequences of domain rearrangements due to the possibility to assess the functional properties of native and artificially created variants using spectroscopic methods and metal tolerance assays. In this study, we have investigated the functional properties of AbiMT4 from the snail Alinda biplicata (Gastropoda, Mollusca), a large MT comprising 10 putative β domains (β39β1), alongside four artificially designed variants differing in domain number, type, or order. Our findings reveal that AbiMT4 is a cadmium-selective protein with a high metal-binding capacity, characterized by structurally and functionally independent domains repeated in tandem along the protein. Our results indicate that due to its modular organization, AbiMT4 remains functional even when the number, type, and order of the domains are significantly altered. Furthermore, we demonstrate that the metal-binding properties of AbiMT4 are not dictated by the overall architecture of the protein but primarily arise from the properties of each individual domain. Using MTs as example, this work provides empirical evidence that domain rearrangements are an effective strategy for exploring new viable sequences and creating novel protein variants subject to adaptive selection. Thus, our study highlights the importance of the modular structure of proteins, as increasing their functional flexibility enhances their evolvability. Additionally, our work demonstrates a simple way to design and model new proteins for predefined functions.
Experimental recombining of repetitive motifs leads to large functional metallothioneins and demonstrates their modular evolvability potential.
(Wiley, 2024-12-14) Dallinger, Reinhard; Pedrini-Martha, Veronika; Burdisso, María Lucía; Capdevila, Mercè; Palacios Bonilla, Òscar; Albalat Rodríguez, Ricard
Protein modularity is acknowledged for promoting the emergence of new protein variants via domain rearrangements. Metallothioneins (MTs) offer an excellent model system for experimentally examining the consequences of domain rearrangements due to the possibility to assess the functional properties of native and artificially created variants using spectroscopic methods and metal tolerance assays. In this study, we have investigated the functional properties of AbiMT4 from the snail Alinda biplicata (Gastropoda, Mollusca), a large MT comprising 10 putative β domains (β39β1), alongside four artificially designed variants differing in domain number, type, or order. Our findings reveal that AbiMT4 is a cadmium-selective protein with a high metal-binding capacity, characterized by structurally and functionally independent domains repeated in tandem along the protein. Our results indicate that due to its modular organization, AbiMT4 remains functional even when the number, type, and order of the domains are significantly altered. Furthermore, we demonstrate that the metal-binding properties of AbiMT4 are not dictated by the overall architecture of the protein but primarily arise from the properties of each individual domain. Using MTs as example, this work provides empirical evidence that domain rearrangements are an effective strategy for exploring new viable sequences and creating novel protein variants subject to adaptive selection. Thus, our study highlights the importance of the modular structure of proteins, as increasing their functional flexibility enhances their evolvability. Additionally, our work demonstrates a simple way to design and model new proteins for predefined functions.
In vitro and in vivo activity of daptomycin plus ceftaroline for the treatment of experimental endocarditis due to Enterococcus faecalis with and without high-level aminoglycoside resistance
(Oxford University Press, 2026-05-01) Cañas, María Alexandra; García González, Javier; Luque Paz, David; Cuervo Requena, Guillermo; Krivak, Filip; Nin Blanch, Judit; Hernández Meneses, Marta; Falces Salvador, Carles; Maristany Bosch, Marta; Perissinotti, Andrés; Vidal, Bàrbara; Tolosana, José M. (José María); Quintana, Eduard; Llopis Pérez, Jaime; Moreno Camacho, Ma. Asunción; García de la Mària, Cristina; Miró Meda, José M. (José María), 1956-; Hospital Clínic Endocarditis Study Group
Objectives Effective alternatives to standard of care treatment for E. faecalis infective endocarditis (EFIE) are needed. Some in vitro studies have suggested daptomycin and ceftaroline have synergistic activity against E. faecalis. We aimed to assess the in vitro and in vivo activity of daptomycin in combination with ceftaroline against E. faecalis clinical isolates with and without high-level of aminoglycoside resistance (HLAR). Materials and methods A panel of six endocarditis-associated E. faecalis isolates were used for time–kill assays at initial standard and high inocula. Daptomycin (10 mg/kg/day intravenously) and daptomycin (10 mg/kg/day iv) plus ceftaroline (600 mg q12 hours intravenous) were compared in vivo using a human-like pharmacokinetic model in two treatment groups using the experimental EFIE model in rabbits. Results The combination of daptomycin plus ceftaroline achieved synergy against all three HLAR and all three non-HLAR strains in time–kill assays at initial standard inoculum. A bactericidal effect was observed in two of the three HLAR E. faecalis isolates. For HLAR EFAE-188, the use of daptomycin plus ceftaroline significantly decreased the bacterial density in vegetations compared with daptomycin alone (median density 5.2 versus 6.7 log10 cfu/g; P = 0.028). For non-HLAR EFAE-468, the bacterial density in vegetations was lower with the combination therapy than with daptomycin alone (median density 5.2 versus 6.8 log10 cfu/g; P = 0.072). Adding ceftaroline prevented the development of daptomycin-resistant E. faecalis isolates in all cases. Conclusions Daptomycin plus ceftaroline represents a promising alternative for treating EFIE. Further clinical studies are needed to confirm these findings.
Multi-ancestry genome-wide association and integrated multi-omics analyses of endometriosisand its clinical manifestations<br />
(Nature Publishing Group, 2026-04-01) Cormand Rifà, Bru; Flores, Idhaliz; Altmae, Signe; Mitjans Niubó, Marina; Cabrera-Mendoza, Brenda; Polimanti, Renato; Koller, Dora; He, Jun; Lokhammer, Solveig; Aranda, Selena; Qiu, Dan; Davtian, David; Chen, Qin; Xu, Ziang; Mao, Zhongzheng; Friligkou, Eleni; Karaca, Sefayet
Endometriosis is a chronic systemic disease affecting ~10%women, yet its geneticbasis and molecular mechanisms remain poorlyunderstood. Hence, we conducted a genome-wide association study of endometriosis and adenomyosis in ~1.4 million women, including 105,869cases, aiming to expand locidiscovery across ancestries, dissect symptom-specific effects and integratemulti-omic data. We identified 80 genomic regions associated with endometriosis risk,including 37 new loci, and 5 of which are alsoassociated with adenomyosis. We identified putativecausal variants underlying over 50 of these associations. Transcriptomic, epigenetic and proteomic analyses across tissueslinked endometriosis risk to pathways involved in cell differentiation, immune and hormonalregulation, tissue remodeling and inflammation. Drug-repurposing analyses highlighted potential treatments currently used for breastcancer, contraception and preterm birthprevention. Endometriosis polygenic risk interacted with abdominal pain, anxiety, migraineand nausea. This study advances understanding of genetic risk factors for endometriosis and provides molecular support for several hypotheses on its pathogenesis.
The Excess of Carriers in Rare Disorders Suggests a Nonpathogenic Effect for Most Variants of Uncertain Significance
(John Wiley & Sons, 2024-11-05) Medaglia, Stefano; Reig-Palou, Jaume; Bellés, Ariadna; Moreno-Ruiz, Nerea; Rodríguez, Jairo; Armengol, Xavier; Aróstegui Gorospe, Juan Ignacio; Armengol, Lluís; Guillén, Juan José; Laayouni, Hafid; Casals López, Ferran
Functional annotation and interpretation of genetic variants are a critical step in genetic diagnosis, as it may lead to personalized therapeutic options and genetic counseling. While the number of confirmed pathogenic genetic variants in an individual is relatively low, the number of variants of uncertain significance (VOUS) can be considerably higher, increasing the number of potential carriers of genetic disorders. Thus, reducing uncertainty and assessing the real effect of VOUS are crucial for clinical and medical genetics. In this study, we evaluated the efficacy of genetic screening technologies in accurately predicting pathogenic variants and their corresponding disease prevalence in a cohort of over 6000 healthy individuals involved in assisted reproduction programs. Using data from 305 genes associated with recessive disorders, we determined the frequency of carriers of pathogenic variants and VOUS in our dataset and compared the predicted prevalence based on this information with reported population prevalence data. The higher predicted prevalence in some disorders when considering VOUS suggests a mostly benign effect.
Unraveling acridine degradation mechanisms in PAH-contaminated soils using DNA-SIP combined with metagenomics and soil transcriptomics
(Elsevier B.V., 2026-04-07) Jordán, Maria; Bustos-Caparros, Esteban; Gago, Juan F.; Zhang, Zhenfa; Tian, Zhenyu; Singleton, David R.; Rosello-Mora, Ramon; Grifoll Ruiz, Magdalena; Vila Grajales, Joaquim
Polycyclic aromatic nitrogen heterocycles (PANHs), also known as azaarenes, are common co-contaminants at sites contaminated with polycyclic aromatic hydrocarbons (PAHs). Recent non-target analysis of PAH- contaminated soil samples has revealed an unexpected abundance and diversity of PANHs, with acridine standing out as a predominant compound within this group. Despite its known toxicity and prevalence in contaminated soils, the microbial communities and biochemical mechanisms responsible for acridine degrada tion remain poorly understood. We conducted DNA-stable isotope probing (DNA-SIP) using newly synthesized uniformly labeled 13 C-acridine to comprehensively assess the bacterial taxa and functional genes involved in acridine biodegradation in a creosote-contaminated soil. Metagenomic analysis of 13 C-enriched DNA from soil incubations identified a member of the genus Sphingobium as the primary acridine degrader. Transcriptomic analysis based on its 16S rRNA gene expression demonstrated a strong correlation with acridine removal from the soil. Shotgun metagenomic sequencing enabled the reconstruction of one metagenome-assembled genome (MAG). Functional annotation of this MAG revealed five gene clusters potentially involved in acridine biodeg radation, and their actual contribution was assessed by gene expression analysis in soil incubations. Based on these findings, we reconstructed the metabolic pathway for putative acridine degradation in PAH-contaminated soil.
Navigating spatio-temporal microbiome dynamics: Environmental factors and trace elements shape the symbiont community of an invasive marine species
(Elsevier Ltd., 2024-06-01) Galià Camps, Carles; Junkin, Liam; Borrallo, Xavier; Carreras Huergo, Carlos; Pascual Damieta, Marta; Turon Barrera, Xavier
The proliferation of marine invasive species is a mounting concern. While the role of microbial communities in invasive ascidian species is recognized, the role of seasonal shifts in microbiome composition remains largely unexplored. We sampled five individuals of the invasive ascidian Styela plicata quarterly from January 2020 to October 2021 in two harbours, examining gills, tunics, and surrounding water. By analysing Amplicon Sequence Variants (ASVs) and seawater trace elements, we found that compartment (seawater, tunic, or gills) was the primary differentiating factor, followed by harbour. Clear seasonal patterns were evident in seawater bacteria, less so in gills, and absent in tunics. We identified compartment-specific bacteria, as well as seasonal indicator ASVs and ASVs correlated with trace element concentrations. Among these bacteria, we found that Endozoicomonas, Hepatoplasma and Rhodobacteraceae species had reported functions which might be necessary for overcoming seasonality and trace element shifts. This study contributes to understanding microbiome dynamics in invasive holobiont systems, and the patterns found indicate a potential role in adaptation and invasiveness.
Modulation of the gut microbiome-adipose tissue axis by maqui supplementation improved insulin resistance and lipid metabolism in mice under a high-fat diet.
(Elsevier Ltd., 2026-03-03) Tume, Rafael; Cruz, Meryl; Sandoval, Viviana; Iglesias-Vejar, Lorena; Sanz Lamora, Héctor; Pérez-Martí, A.; Torres-Oteros, Daniel; Cubedo-Cullere, Marta; Carmona Pontaque, Francesc; Martínez Huélamo, Miriam; Marrero González, Pedro F.; Haro, D.; Canudas Puig, Sílvia; Andrés Lacueva, Ma. Cristina; Relat, Joana; Meroño, Tomás
To assess the impact of maqui (Aristotelia chilensis) supplementation on the gut microbiome-adipose tissue axis, and to associate it with gene expression changes in white adipose tissue (WAT) in mice fed a high-fat diet. Our hypothesis is that the gut microbiome-adipose tissue axis will be involved in Maqui's effect on WAT browning. Twenty-nine 4-week-old C57BL/6 J mice were randomly assigned to a high-fat diet (HFD, n = 15) or HFD + Maqui (n = 14) for 16 weeks. Plasma samples were analyzed using an UPLC-QTRAP exposome-based metabolomics method. Gut microbiome was studied by fecal 16S rRNA gene sequencing. Gene expression in WAT was assessed by real-time PCR. Data were analyzed by multivariate methods and integrated through multiomics analyses. Maqui supplementation induced an increase in Lactobacillus, Lactococcus and Bifidobacterum and a reduction in Desulfovibrium, and Acetatifactor. Out of 19 metabolites altered by maqui supplementation, 9 were derived from gut bacterial fermentation of anthocyanins. Increases in L. gasseri and L. johnsonii in the gut were associated to increased production of phenyllactic acid, 4-O-methylgallic acid, and 3-(3′-hydroxyphenyl)-γ-valerolactone. Integrative analysis revealed a concerted role of Lactobacillus spp. and its ability to ferment maqui polyphenols, along with increased expression of Chrebpb, Pgc1a and Ucp1 in WAT. Enrichment of Lactobacillus gasseri and johnsonii and exposure to 2-hydroxybenzoic acid derived from polyphenols fermentation are evidences of the involvment of the gut-microbiome-adipose tissue axis in WAT browning induced by maqui.
Flax biorefining for paper production
(Springer Verlag, 2024-05-01) Cabañas-Romero, L. Verónica; Cusola, Oriol; Buruaga-Ramiro, Carolina; Valls, Cristina; Roncero, M. Blanca; Valenzuela Mayorga, Susana Valeria
In this work, we assessed the potential of Cel6D, a recently reported exocellulase from Paenibacillus barcinonensis, as a biorefining agent for flax pulp. Pulp fibers were treated with this enzyme, Cel9B (an endocellulase previously shown to possess biorefining action) and the two in combination. Samples of biorefined flax pulp were mechanically refined to obtain handsheets. All three biorefining treatments decreased air permeance in the handsheets. Cel9B increased tensile index and folding endurance, and the Cel6D − Cel9B combination increased tensile index and burst index but also resulted in markedly decreased tear index and folding endurance. On the other hand, Cel6D increased tensile index and burst index; also, more importantly, it increased tear resistance, albeit slightly, relative to the other two treatments. The results of this work can be useful to understand the differential effects of exocellulases and endocellulases as biorefining tools and open up new avenues for exploring their use in other biotechnological applications.
Genetic contribution to the comorbidity between attention-deficit/hyperactivity disorder and substance use disorders
(Elsevier B.V., 2024-02-03) Koller, Dora; Mitjans Niubó, Marina; Kouakou, Manuela; Friligkou, Eleni; Cabrera-Mendoza, Brenda; Deak, Joseph; Llonga, Natalia; Pathak, Gita A.; Stiltner, Brendan; Lokhammer, Solveig; Levey, Daniel; Zhou, Hang; Hatoum, Alexander; Kember, Rachel; Kranzler, Henry; Stein, Murray; Corominas Castiñeira, Roser; Demontis, D.; Soler Artigas, María; Ramos Quiroga, Josep Antoni; Gelernter, Joel; Ribasés Haro, Marta; Cormand Rifà, Bru; Polimanti, Renato
We characterized the genetic architecture of the attention-deficit hyperactivity disorder-substance use disorder(ADHD-SUD) relationship by investigating genetic correlation, causality, pleiotropy, and common polygenic risk.Summary statistics from genome-wide association studies (GWAS) were used to investigate ADHD (Neff =51,568), cannabis use disorder (CanUD, Neff = 161,053), opioid use disorder (OUD, Neff = 57,120), problematicalcohol use (PAU, Neff = 502,272), and problematic tobacco use (PTU, Neff = 97,836). ADHD, CanUD, and OUDGWAS meta-analyses included cohorts with case definitions based on different diagnostic criteria. PAU GWAScombined information related to alcohol use disorder, alcohol dependence, and the items related to alcohol problematic consequences assessed by the alcohol use disorders identification test. PTU GWAS was generated amulti-trait analysis including information regarding Fagerstr¨om Test for Nicotine Dependence and cigarettes perday. Linkage disequilibrium score regression analyses indicated positive genetic correlation with CanUD, OUD,PAU, and PTU. Genomic structural equation modeling showed that these genetic correlations were related to twolatent factors: one including ADHD, CanUD, and PTU and the other with OUD and PAU. The evidence of a causaleffect of PAU and PTU on ADHD was stronger than the reverse in the two-sample Mendelian randomizationanalysis. Conversely, similar strength of evidence was found between ADHD and CanUD. CADM2 rs62250713was a pleiotropic SNP between ADHD and all SUDs. We found seven, one, and twenty-eight pleiotropic variantsbetween ADHD and CanUD, PAU, and PTU, respectively. Finally, OUD, CanUD, and PAU PRS were associatedwith increased odds of ADHD. Our findings demonstrated the contribution of multiple pleiotropic mechanisms tothe comorbidity between ADHD and SUDs.
Structure and mechanistic basis of NrdR, a bacterial master regulator of ribonucleotide reduction
(Elsevier B.V., 2026-02-04) Pedraz López, Lucas; Szura, Arkadiusz; Schmitz, Claus; Rubio Canalejas, Alba; Martínez Mateos, Ángela; Santella, Anthony; Gomila Lluch, Gabriel; Calò, Annalisa; Solà, Maria; Torrents Serra, Eduard
Ribonucleotide reductases (RNRs) are the essential enzymes responsible for synthesizing dNTPs, the building blocks of DNA. In bacteria, the entire RNR network is controlled by the master regulator NrdR. As a regulator of an essential pathway with no eukaryotic equivalent, NrdR is a promising antimicrobial target. Recent structural studies have outlined a mechanism of action for NrdR, in which ATP and dATP induce changes in the protein quaternary structure, regulating RNR repression. However, due to a lack of functional studies linking the known structures to their biological roles, the activation mechanism of NrdR is not yet fully understood. Here, we conducted a comprehensive study of NrdR in Escherichia coli and Pseudomonas aeruginosa. We delimited the NrdR regulon, combining transcriptomics and motif-based sequence analysis. We crystallized E. coli NrdR and identified the protein-protein interfaces involved in its oligomerization, including strong interactions between NrdR dimers to form tetramers, and less stable interfaces connecting such tetramers. We examined the variability of the quaternary structures of NrdR depending on the bound nucleotides by SEC-MALS and atomic force microscopy, and correlated structure to function using point mutations, EMSAs, and in vitro transcription assays. Overall, our results demonstrate the mechanism used by NrdR to modulate its quaternary structure and activity, deciphering essential interactions between subunits, and paving the way for targeted antimicrobial therapies.
Galleria mellonella as a simple yet reliable in vivo model for nanotoxicology: Techniques and applications
(John Wiley & Sons, 2025-09-01) Blanco-Cabra, Núria; Admella, Joana; Torrents Serra, Eduard
Nanomaterials are a rapidly advancing tool with applications across various scientific fields. However, their interactions with living organisms have raised numerous safety concerns, making it crucial to develop reliable models to predict and evaluate associated toxicity effects. Traditional in vitro assays fail to mimic the true physiological responses of living organisms to nanomaterials, whereas murine and other in vivo models are time-consuming, costly, and ethically controversial. The greater wax moth, Galleria mellonella, has emerged as a promising in vivo model for nanotoxicology, serving as an effective bridge between in vitro and in vivo mammalian testing. This model combines simplicity and ethical viability with a human-conserved innate immune system, making it ideal for immunotoxicity testing. While it cannot fully replace more complex animal models, G. mellonella represents a valuable alternative for early-stage nanotoxicology screening and deserves greater recognition and integration into toxicological research. In this review, we examine all the methodologies and applications of G. mellonella in nanotoxicological studies, highlighting its potential as a reliable and ethical model for assessing nanomaterial safety.
In Vitro Activity of Ampicillin Plus Ceftriaxone Against Non-faecalis and Non-faecium Enterococcal Isolates With/Without VanC Phenotype: Clinical Implications for Infective Endocarditis.
(MDPI, 2024-12-05) García González, Javier; Cañas, María Alexandra; Cuervo Requena, Guillermo; Hernández Meneses, Marta; Verdejo, Miguel Ángel; Bodro, Marta; Díez de los Ríos, Javier; Gasch, Oriol; Ribera, Alba; Falces Salvador, Carles; Perissinotti, Andrés; Vidal, Bàrbara; Quintana, Eduard; Moreno Camacho, Ma. Asunción; Piquet, Maria; Roca Subirà, Ignasi; Fernández Pittol, Mariana José; San José Villar, Sol María; García de la Mària, Cristina; Miró Meda, José M. (José María), 1956- ; Hospital Clínic Endocarditis Study Group
1) Background: Alternative antibiotics are needed to treat infective endocarditis (IE) caused by non-faecalis/non-faecium enterococci; we aimed to assess the in vitro activity of ampicillin plus ceftriaxone (AMP + CTR) against these enterococci and to describe its clinical efficacy in IE cases. (2) Methods: Time–kill curves with standard (ISI) and high (IHI) inocula were performed to test VanC isolates [3 E. casseliflavus (ECAS) and 1 E. gallinarum (EGALL)] and non-VanC isolates [1 E. durans (EDUR), 1 E. hirae (EHIR) and 1 E. raffinosus (ERAF)]. The narrative literature review of IE cases treated with AMP + CTR was analyzed alongside three study cases. Clinical outcomes were relapse and death. (3) Results: Ampicillin plus gentamicin (AMP + GEN) showed synergistic and bactericidal activity against most isolates. AMP + CTR was synergistic at ISI for EGALL, EDUR, and EHIR and bactericidal against EHIR. At IHI, indifferent activity was observed for all isolates. In IE cases treated with AMP + CTR, it was only effective for EDUR and EHIR. Clinical information for EGALL IE is lacking. For IE caused by ECAS and ERAF, AMP + CTR seems suboptimal or ineffective, respectively. (4) AMP + CTR cannot be recommended for treating IE due to ECAS/ERAF. In contrast, this combination was effective in IE caused by EDUR/EHIR and could be recommended.
Development of High-Level Daptomycin Resistance in Abiotrophia and Granulicatella Species Isolates from Patients with Infective Endocarditis
(American Society for Microbiology, 2021-09-17) Cañas, María Alexandra; Téllez, Adrián; García de la Mària, Cristina; Dahl, Anders; García González, Javier; Hernández Meneses, Marta; Almela, M. (Manel); Ambrosioni, Juan; Falces Salvador, Carles; Quintana, Eduard; Vidal, Bàrbara; Perissinotti, Andrés; Tolosana, José M. (José María); Sandoval, Elena; Pericàs, Juan M.; Moreno Camacho, Ma. Asunción; Miró Meda, José M. (José María), 1956- ; Hospital Clínic Endocarditis Team Investigator
Abiotrophia and Granulicatella species are fastidious organisms, representing the causative agents of ∼1% to 3% of cases of infective endocarditis (IE). Little is known about the optimal antibiotic treatment for these species, and daptomycin has been suggested as a therapeutic option. We describe the antimicrobial profiles of Abiotrophia and Granulicatella IE isolates, investigate high-level daptomycin resistance (HLDR) development, and evaluate daptomycin activity in combination therapy. In vitro studies with 16 IE strains (6 Abiotrophia defectiva strains, 9 Granulicatella adiacens strains, and 1 G. elegans strain) were performed using microdilution to determine MICs and time-kill methodology to evaluate combination therapy. Daptomycin nonsusceptibility (DNS) (MIC ≥ 2 mg/liter) and HLDR (MIC ≥ 256 mg/liter) were based on existing Clinical and Laboratory Standards Institute (CLSI) breakpoints for viridans group streptococci. All isolates were susceptible to vancomycin: G. adiacens was more susceptible to penicillin and ampicillin than A. defectiva (22% versus 0% and 67% versus 33%) but less susceptible to ceftriaxone and daptomycin (56% versus 83% and 11% versus 50%). HLDR developed in both A. defectiva (33%) and G. adiacens (78%) after 24 h of exposure to daptomycin. Combination therapy did not prevent the development of daptomycin resistance with ampicillin (2/3 strains), gentamicin (2/3 strains), ceftriaxone (2/3 strains), or ceftaroline (2/3 strains). Once developed, HLDR was stable for a prolonged time (>3 weeks) in G. adiacens, whereas in A. defectiva, HLDR reversed to the baseline MIC at day 10. This study is the first to demonstrate rapid HLDR development in Abiotrophia and Granulicatella species in vitro. Resistance was stable, and most combination therapies did not prevent it.

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