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Self-assembling peptides (SAPs) have gained significant attention in biomedicine because of their unique properties and ability to undergo molecular self-assembly driven by non-covalent interactions. By manipulating their composition and structure, SAPs can form well-ordered nanostructures with enhanced selectivity, stability and biocompatibility. SAPs offer advantages such as high chemical and biological diversity and the potential for functionalization. However, studies concerning its potentially toxic effects are very scarce, a limitation that compromises its potential translation to humans. This study investigates the potentially toxic effects of six different SAP formulations composed of natural amino acids designed for nervous tissue engineering and amenable to ready cross-linking boosting their biomechanical properties. All methods were performed in accordance with the relevant guidelines and regulations. A wound-healing assay was performed to evaluate how SAPs modify cell migration. The results in vitro demonstrated that SAPs did not induce genotoxicity neither skin sensitization. In vivo, SAPs were well-tolerated without any signs of acute systemic toxicity. Interestingly, SAPs were found to promote the migration of endothelial, macrophage, fibroblast, and neuronal-like cells in vitro, supporting a high potential for tissue regeneration. These findings contribute to the development and translation of SAP-based biomaterials for biomedical applications.

The dynamics of SARS-CoV-2 transmission are influenced by a variety of factors, including social restrictions and the emergence of distinct variants. In this study, we delve into the origins and dissemination of the Alpha, Delta, and Omicron variants of concern in Galicia, northwest Spain. For this, we leveraged genomic data collected by the EPICOVIGAL Consortium and from the GISAID database, along with mobility information from other Spanish regions and foreign countries. Our analysis indicates that initial introductions during the Alpha phase were predominantly from other Spanish regions and France. However, as the pandemic progressed, introductions from Portugal and the USA became increasingly significant. Notably, Galicia’s major coastal cities emerged as critical hubs for viral transmission, highlighting their role in sustaining and spreading the virus. This research emphasizes the critical role of regional connectivity in the spread of SARS-CoV-2 and offers essential insights for enhancing public health strategies and surveillance measures.

Scientific advisory bodies provide scientific advice for sustainable fisheries management based on the precautionary approach and maximum sustainable yield (MSY) reference points, such as spawning stock biomass (SSB) value B, and fishing mortality giving MSY, F. The lack of a stock-recruitment function (SRF) to identify a clear breakpoint B has recently emerged in important stock collapses. It also precludes the use of equilibrium-based methods to analyze the sustainability of F. Considering a hockey stick (HS) SRF, we propose here an equilibrium-based method that characterizes the equilibriums, their stability properties, transient dynamics, and changes in productivity (including age-specific natural mortality rates). We show that these relevant factors, not taken into account in standard methods, should play a central role in fisheries management and conservation. Considering the Northern cod stock (NCS) (Gadus morhua) by way of illustration, we properly estimate the HS and its associated B. We find that the HS fitted by the Fisheries Library in R underestimates B. Additionally, we determine the levels of productivity (medium-low or medium-high), and their corresponding growth rates of the SSB, which are consistent with the observed population dynamics. We find that the NCS was managed during the 1980s under myopic (unsustainable) harvest control rules, neglecting high age-specific natural mortality rates. We also find that recovery of the NCS remains a distant prospect, despite the current stable, positive equilibrium (sustainable F).

Immunotherapy treatments aim to modulate the host’s immune response to either mitigate it in inflammatory/autoimmune disease or enhance it against infection or cancer. Among different immunotherapies reaching clinical application during the last years, chimeric antigen receptor (CAR) immunotherapy has emerged as an effective treatment for cancer where different CAR T cells have already been approved. Yet their use against infectious diseases is an area still relatively poorly explored, albeit with tremendous potential for research and clinical application. Infectious diseases represent a global health challenge, with the escalating threat of antimicrobial resistance underscoring the need for alternative therapeutic approaches. This review aims to systematically evaluate the current applications of CAR immunotherapy in infectious diseases and discuss its potential for future applications. Notably, CAR cell therapies, initially developed for cancer treatment, are gaining recognition as potential remedies for infectious diseases. The review sheds light on significant progress in CAR T cell therapy directed at viral and opportunistic fungal infections.

Quick estimates of fluid-induced subsurface deformation are helpful to assess the land uplift/subsidence and to reveal precursors of induced seismicity. Here, we adopt the inclusion theory and Green's function to develop a closed-form solution in a half space for the poroelastic response of a reservoir compartmentalized by an intersecting fault that can be offset and either permeable or impermeable. Simulated results reveal that (1) fault permeability mainly impacts the spatial distribution of displacement while its effect on displacement magnitude is small; (2) ground displacement slightly increases with fault dip while slightly decreases with increasing fault offset; in contrast, reservoir geometry shows a stronger effect than fault geometry: the ground displacement is proportional to the vertical and lateral depth ratios, defined as the ratios of reservoir thickness (h) and width (w) to reservoir depth (D), respectively; (3) the maximum vertical displacement is the double of the horizontal one regardless of fault permeability, fault and reservoir geometries, and mechanical parameters. Comparing the solution in a half space with that in a full space shows that neglecting the free surface underestimates the poroelastic displacement in the overburden. The validity of full-space solutions can be assessed with the product of the lateral and vertical depth ratios, i.e., wh/D2. The full-space solutions become valid when wh/D2 decreases to an intrinsic threshold. This threshold may range from 0.01 to 0.02 for displacement, and its specific value depends on the field background and demands of projects, but can be estimated based on our solution. It is larger for stress than for displacement, and wh/D2 ≤ 0.1 is recommended as a general condition for neglecting the free-surface effects on induced stress. The analytical solution represents a useful tool for estimating ground deformation and for gaining insights of reservoir and fault geometries by analyzing surface deformati

Gene sequencing in back of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is the current approach for discriminating infections produced by different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in the clinic. However, sequencing is often a time-consuming step, which hinders the deployment of a very fast response during a pandemic. Here, we propose to run a CRISPR-Cas12a reaction after completing the RT-qPCR and in the very same pot to detect with high specificity genetic marks characterizing variants of concern. A crRNA was appropriately designed to detect the S gene of the SARS-CoV-2 Omicron BA.1 variant. A significant response with >20-fold dynamic range was obtained for the Omicron BA.1 S gene, while the Delta S gene did not produce any detectable signal. The sensitivity of the method was analyzed with a series of diluted samples and different Cas12a nucleases. A correlation between the RT-qPCR CT values and the CRISPR-Cas12a reaction signals was observed. Variant discrimination with the CRISPR-Cas12a reaction was possible in some minutes with high accuracy from patient samples. In conclusion, CRISPR-Cas systems seem ready to be exploited in the clinic to boost personalized diagnoses and accelerate epidemiological surveillance in a cost-effective way.

Since its introduction in the human population, SARS-CoV-2 has evolved into multiple clades, but the events in its intrahost diversification are not well understood. Here, we compare three-dimensional (3D) self-organized neural haplotype maps (SOMs) of SARS-CoV-2 from thirty individual nasopharyngeal diagnostic samples obtained within a 19-day interval in Madrid (Spain), at the time of transition between clades 19 and 20. SOMs have been trained with the haplotype repertoire present in the mutant spectra of the nsp12- and spike (S)-coding regions. Each SOM consisted of a dominant neuron (displaying the maximum frequency), surrounded by a low-frequency neuron cloud. The sequence of the master (dominant) neuron was either identical to that of the reference Wuhan-Hu-1 genome or differed from it at one nucleotide position. Six different deviant haplotype sequences were identified among the master neurons. Some of the substitutions in the neural clouds affected critical sites of the nsp12-nsp8-nsp7 polymerase complex and resulted in altered kinetics of RNA synthesis in an in vitro primer extension assay. Thus, the analysis has identified mutations that are relevant to modification of viral RNA synthesis, present in the mutant clouds of SARS-CoV-2 quasispecies. These mutations most likely occurred during intrahost diversification in several COVID-19 patients, during an initial stage of the pandemic, and within a brief time period.

The eukaryotic translation initiation protein eIF5A is a highly conserved and essential factor that plays a critical role in different physiological and pathological processes including stress response and cancer. Different proteomic studies suggest that eIF5A may be a small ubiquitin-like modifier (SUMO) substrate, but whether eIF5A is indeed SUMOylated and how relevant is this modification for eIF5A activities are still unknown.

The aim of this study is to show the optimal arrangement of a measurement system for estimating the thermal conductivity of thin films from temperature profiles. For this purpose, two different experimental setup systems, with square and circular cross sections, were designed to estimate the thermal conductivity of thin films and, in particular, of two ion exchange membranes. Both systems were placed horizontally and vertically in order to evaluate the best orientation to more accuratelydetermine thermal conductivity. A three-dimensional numerical simulation was performed using Comsol Multiphysics to predict the heat flow and temperature gradient and to evaluate the effect of the geometry and the orientation on the contact resistances. Each system was first calibrated without the membrane inside in order to estimate all the necessary thermal properties of the different materials of the model. Next, the membrane was placed inside the model, so that the model now includes the thermal conductivity of the membrane as the only unknown parameter. The numerical results were compared with the various measured temperature profiles to estimate the thermal conductivity. The thermal conductivity values of the well-known Nafion 117 membrane and other thicker membrane were determined. A very good agreement with reliable literature values was obtained. The approach presented here, combining experimental and simulated temperature profiles, may provide the basis for a practical alternative to better estimate the thermal conductivity of thin films.

En este trabajo, analizaremos el poemario El príncipe rojo (2005) de la madrileña Almudena Guzmán, reparando especialmente los modos en los que se aborda el erotismo. Para esto, dividiremos nuestro estudio en varias secciones que recuperarán los distintos temas a los que la autora acude para hablar de él. Al interior de cada una de ellas, nos proponemos, no solo realizar un análisis textual de las imágenes diseñadas, sino también tender puentes con la tradición literaria y cultural para evaluar cuáles son los referentes que se ponen en juego en cada uno de los conjuntos temáticos. Asimismo, otro de nuestros objetivos será revisar si todas estas configuraciones del erotismo persisten en otros poemarios de la autora o si, por el contrario, son exclusivas de El príncipe rojo (2005)., In this paper, we will analyse the collection of poems El príncipe rojo (2005) by the Madridborn Almudena Guzmán, paying special attention to the ways in which eroticism is approached. For this purpose, we will divide our study into several sections that will recover the different themes that are linked to eroticism in the collection. Within each of these sections, we intend not only to carry out a textual analysis of the images designed, but also to build bridges with the literary and cultural tradition in order to evaluate which are the referents that are put into play in each of the thematic groups. Likewise, another of our objectives will be to review whether all these configurations of eroticism persist in other collections of poems by the author or whether, on the contrary, they are exclusive to El príncipe rojo (2005).

Recurrent disease outbreaks caused by different viruses, including the novel respiratory virus SARS-CoV-2, are challenging our society at a global scale; so versatile virus detection methods would enable a calculated and faster response. Here, we present a novel nucleic acid detection strategy based on CRISPR-Cas9, whose mode of action relies on strand displacement rather than on collateral catalysis, using the Streptococcus pyogenes Cas9 nuclease. Given a preamplification process, a suitable molecular beacon interacts with the ternary CRISPR complex upon targeting to produce a fluorescent signal. We show that SARS-CoV-2 DNA amplicons generated from patient samples can be detected with CRISPR-Cas9. We also show that CRISPR-Cas9 allows the simultaneous detection of different DNA amplicons with the same nuclease, either to detect different SARS-CoV-2 regions or different respiratory viruses. Furthermore, we demonstrate that engineered DNA logic circuits can process different SARS-CoV-2 signals detected by the CRISPR complexes. Collectively, this CRISPR-Cas9 R-loop usage for the molecular beacon opening (COLUMBO) platform allows a multiplexed detection in a single tube, complements the existing CRISPR-based methods, and displays diagnostic and biocomputing potential.

Bacteria of the genus Streptomyces have a plethora of transcriptional regulators, among which the xenobiotic response element (XRE) plays an important role. In this organism, XRE regulators are often followed downstream by small proteins of unknown function containing a DUF397 domain. It has been proposed that XRE/DUF397 pairs constitute type II toxin–antitoxin (TA) systems. However, previous work carried out by our group has shown that one of these systems is a strong activator of antibiotic production in S. coelicolor and other Streptomyces species. In this work, we have studied the overexpression of fourteen XRE/DUF397 pairs present in the S. coelicolor genome and found that none behave as a type II TA system. Instead, they act as pleiotropic regulators affecting, in a dependent manner, antibiotic production and morphological differentiation on different culture media. After deleting, individually, six XRE/DUF397 pairs (those systems producing more notable phenotypic changes when overexpressed: SCO2246/45, SCO2253/52, SCO4176/77, SCO4678/79, SCO6236/35, and SCO7615/16), the pair SCO7615/16 was identified as producing the most dramatic differences as compared to the wild-type strain. The SCO7615/16 mutant had a different phenotype on each of the media tested (R2YE, LB, NMMP, YEPD, and MSA). In particular, on R2YE and YEPD media, a bald phenotype was observed even after 7 days, with little or no actinorhodin (ACT) production. Lower ACT production was also observed on LB medium, but the bacteria were able to produce aerial mycelium. On NMMP medium, the mutant produced a larger amount of ACT as compared with the wild-type strain.

Nanoparticles of poly(3-hexylthiophene), P3HT(NP), uniquely enable the preparation of stable dispersions in environmentally-friendly media and thus offer a sustainable liquid phase fabrication of electrochromic device structures. In this work, we assess the electrochromic performance of P3HT(NP) films spray-coated from either tetrahydrofuran (THF)-water or chloroform (CHCl3)-ethanol dispersions on ITO substrates. The nanoparticle films exhibit consistent and reproducible high optical contrast values of around 50 %, t90-switching speeds of about 0.45 s and a cycling stability of approximately 200 cycles for a 20 % performance retention, independent of the solvent being used. Conversely, non-nanostructured P3HT films spray-coated from THF or CHCl3 reveal a strong solvent dependent variability in their electrochromic behavior presenting low optical contrast, high switching speeds and fast degradation rates in the case of CHCl3. The solvent independent electrochromic characteristics of P3HT nanoparticle films is related to a consistent availability of accessible electroactive sites provided by a homogeneous porous P3HT network structure formed on the underlying substrate, as probed by SEM and profilometric studies. Our findings reveal that the use of nanoparticles of P3HT and its environmentally benign liquid phase processing, a concept which is extendable to other electrochromic polymers, opens a sustainable pathway toward the large-area fabrication of electrochromic device structures with favorable and consistent performance parameters.

The use of active coatings in fresh food packaging is an innovative technique that optimizes the functional properties of films, resulting in a longer product shelf life and reduced food waste. But, which is more sustainable, active packaging (AP) or conventional packaging (CP) for the packaging of fresh-cut products? To answer this research question, this study analyzes the environmental performance of AP during its life cycle for packaging a minimally processed fresh salad mix compared with CP, in terms of its manufacture and use. The AP is a bag that includes a bioactive component, oregano essential oil (OEO), which is an inhibitor of microbial growth, incorporated into an ethylene vinyl alcohol copolymer (EVOH) coating on a conventional polypropylene (PP) film. To this end, a Life Cycle Assessment (LCA) was carried out based on ISO 14040 and 14044, using the ReCiPe methodology. The results showed that using active packaging has a beneficial affect, reducing the amount of produced food by 30% compared with conventional packaging over the same period. The reductions in the studied impact categories were greater than 50% in most of them, with a 62% reduction in global warming. The proposed sensitivity analysis showed the difference between the disposal or treatment of waste generated by the packaging production process and the packaged product, indicating that this step is of great importance for the environmental impacts and sustainability of this process. In 80% of the scenarios analyzed, the AP achieved better results than the CP in terms of damage categories.

Mathematical modeling has been fundamental to achieving near real-time accurate forecasts of the spread of COVID-19. Similarly, the design of non-pharmaceutical interventions has played a key role in the application of policies to contain the spread. However, there is less work done regarding quantitative approaches to characterize the impact of each intervention, which can greatly vary depending on the culture, region, and specific circumstances of the population under consideration. In this work, we develop a high-resolution, data-driven agent-based model of the spread of COVID-19 among the population in five Spanish cities. These populations synthesize multiple data sources that summarize the main interaction environments leading to potential contacts. We simulate the spreading of COVID-19 in these cities and study the effect of several non-pharmaceutical interventions. We illustrate the potential of our approach through a case study and derive the impact of the most relevant interventions through scenarios where they are suppressed. Our framework constitutes a first tool to simulate different intervention scenarios for decision-making.

Diverse modifications of the original morphological features occur throughout the taphonomic history of osteological remains, which may lead in erroneous interpretations about the formation of an accumulation as well as taxonomic misidentifications. Here, we present a neo-taphonomic study in order to analyze and interpret the modifications generated by digestion on osteoderms of the armadillo Dasypus novemcinctus obtained from scats produced by Puma concolor. Results reveal intense breakage and modifications of the articular and broken edges, dorsal surface, bone tissues, and ornamentation pattern of the osteoderms. This work describes for the first time the modifications caused by digestion in armadillo osteoderms, improving the knowledge of preservation of this type of skeletal element and providing a modern analog that can be used to distinguish archeological and paleontological accumulations formed by predators from those generated by other processes. The recognition that digestion modifies the original ornamentation pattern is particularly significant because ornamentation features are used in nearly all taxonomic and phylogenetic studies of fossil cingulates. We use this new information to re-evaluate osteoderms recovered from carnivore coprolites of the classic Middle Miocene La Venta site (Colombia), which formed the basis for recognizing and characterizing the dasypodid species Nanoastegotherium prostatum. We highlight the importance of knowing with certainty the origin and taphonomic history of remains since, in the particular case of cingulates, taxonomic identification also has important biostratigraphic, paleoecological, paleoenvironmental, and paleobiogeo-graphical implications.

MicroRNAs (miRNAs) encapsulated in extracellular vesicles (EVs) are potential diagnostic and prognostic biomarkers. However, discrepancies in miRNA patterns and their validation are still frequent due to differences in sample origin, EV isolation, and miRNA sequencing methods. The aim of the present study is to find a reliable EV isolation method for miRNA sequencing, adequate for clinical application. To this aim, two comparative studies were performed in parallel with the same human plasma sample: (i) isolation and characterization of EVs obtained using three procedures: size exclusion chromatography (SEC), iodixanol gradient (GRAD), and its combination (SEC+GRAD) and (ii) evaluation of the yield of miRNA sequences obtained using NextSeq 500 (Illumina) and three miRNA library preparation protocols: NEBNext, NEXTFlex, and SMARTer smRNA-seq. The conclusion of comparison (i) is that recovery of the largest amount of EVs and reproducibility were attained with SEC, but GRAD and SEC+GRAD yielded purer EV preparations. The conclusion of (ii) is that the NEBNext library showed the highest reproducibility in the number of miRNAs recovered and the highest diversity of miRNAs. These results render the combination of GRAD EV isolation and NEBNext library preparation for miRNA retrieval as adequate for clinical applications using plasma samples.

We report new results on the translational-rotational (T-R) states of the CO2 molecule inside the sI clathrate-hydrate cages. We adopted the multiconfiguration time-dependent Hartree methodology to solve the nuclear molecular Hamiltonian, and to address issues on the T-R couplings. Motivated by experimental X-ray observations on the CO2 orientation in the D and T sI cages, we aim to evaluate the effect of the CO2 -water interaction on quantum dynamics. Thus, we first compared semiempirical and ab initio-based pair interaction model potentials against first-principles DFT-D calculations for ascertaining the importance of nonadditive many-body effects on such guest-host interactions. Our results reveal that the rotational and translational excited states quantum dynamics is remarkably different, with the pattern and density of states clearly affected by the underlying potential model. By analyzing the corresponding the probability density distributions of the calculated T-R eigenstates on both semiempirical and ab initio pair CO2 -water nanocage potentials, we have extracted information on the altered CO2 guest local structure, and we discussed it in connection with experimental data on the orientation of the CO2 molecule in the D and T sI clathrate cages available from neutron diffraction and 13C solid-state NMR studies, as well as in comparison with previous molecular dynamics simulations. Our calculations provide a very sensitive test of the potential quality by predicting the low-lying T-R states and corresponding transitions for the encapsulated CO2 molecule. As such spectroscopic observables have not been measured so far, our results could trigger further detailed experimental and theoretical investigations leading to a quantitative description of the present guest-host interactions.

The standard-of-care treatment of T-cell acute lymphoblastic leukaemia (T-ALL) with chemotherapy usually achieves reasonable rates of initial complete response. However, patients who relapse or do not respond to conventional therapy show dismal outcomes, with cure rates below 10% and limited therapeutic options. To ameliorate the clinical management of these patients, it is urgent to identify biomarkers able to predict their outcomes. In this work, we investigate whether NRF2 activation constitutes a biomarker with prognostic value in T-ALL. Using transcriptomic, genomic, and clinical data, we found that T-ALL patients with high NFE2L2 levels had shorter overall survival. Our results demonstrate that the PI3K-AKT-mTOR pathway is involved in the oncogenic signalling induced by NRF2 in T-ALL. Furthermore, T-ALL patients with high NFE2L2 levels displayed genetic programs of drug resistance that may be provided by NRF2-induced biosynthesis of glutathione. Altogether, our results indicate that high levels of NFE2L2 may be a predictive biomarker of poor treatment response in T-ALL patients, which would explain the poor prognosis associated with these patients. This enhanced understanding of NRF2 biology in T-ALL may allow a more refined stratification of patients and the proposal of targeted therapies, with the ultimate goal of improving the outcome of relapsed/refractory T-ALL patients.

Esta base de datos está destinada a hacer un recuento y a analizar la presencia de los artistas y espectáculos flamencos en Argentina y México, preferentemente a partir de 1936. Se divide en cuatro apartados: los dos primeros prestan atención a los casos de los artistas asentados en Argentina y México. Asimismo, se han incluido en esta nómina a escritores considerados representantes de los estudios flamencos transatlánticos o que tomaron el flamenco como un motivo creativo. Los apartados tercero y cuarto desglosan los espectáculos musicales o teatrales vinculados al flamenco o, al menos, al costumbrismo andaluz que en esos países tuvieron lugar. En cuanto a su estado actual, consideramos que la base de datos se encuentra en proceso. Por ello, agradecemos cualquier observación que nos puedan hacer llegar para complementarla o mejorarla. Pueden escribir en este sentido a emilio.gallardo@csic.es, [Description of methods used for collection/generation of data] Revisión de archivos, hemerotecas y bibliotecas físicas y digitales.

Most cellular proteins involved in genome replication are conserved in all eukaryotic lineages including yeast, plants and animals. However, the mechanisms controlling their availability during the cell cycle are less well defined. Here we show that the Arabidopsis genome encodes for two ORC1 proteins highly similar in amino acid sequence and that have partially overlapping expression domains but with distinct functions. The ancestral ORC1b gene, present before the partial duplication of the Arabidopsis genome, has retained the canonical function in DNA replication. ORC1b is expressed in both proliferating and endoreplicating cells, accumulates during G1 and is rapidly degraded upon S-phase entry through the ubiquitin-proteasome pathway. In contrast, the duplicated ORC1a gene has acquired a specialized function in heterochromatin biology. ORC1a is required for efficient deposition of the heterochromatic H3K27me1 mark by the ATXR5/6 histone methyltransferases. The distinct roles of the two ORC1 proteins may be a feature common to other organisms with duplicated ORC1 genes and a major difference with animal cells.

Administration of neutralizing antibodies (nAbs) has proved to be effective by providing immediate protection against SARS-CoV-2. However, dual strategies combining virus neutralization and immune response stimulation to enhance specific cytotoxic T cell responses, such as dendritic cell (DC) cross-priming, represent a promising field but have not yet been explored. Here, a broadly nAb, TNT, are first generated by grafting an anti-RBD biparatopic tandem nanobody onto a trimerbody scaffold. Cryo-EM data show that the TNT structure allows simultaneous binding to all six RBD epitopes, demonstrating a high-avidity neutralizing interaction. Then, by C-terminal fusion of an anti-DNGR-1 scFv to TNT, the bispecific trimerbody TNTDNGR-1 is generated to target neutralized virions to type 1 conventional DCs (cDC1s) and promote T cell cross-priming. Therapeutic administration of TNTDNGR-1, but not TNT, protects K18-hACE2 mice from a lethal SARS-CoV-2 infection, boosting virus-specific humoral responses and CD8+ T cell responses. These results further strengthen the central role of interactions with immune cells in the virus-neutralizing antibody activity and demonstrate the therapeutic potential of the Fc-free strategy that can be used advantageously to provide both immediate and long-term protection against SARS-CoV-2 and other viral infections.

[Background]: C3G is a guanine nucleotide exchange factor (GEF) that activates Rap1 to promote cell adhesion. Resting C3G is autoinhibited and the GEF activity is released by stimuli that signal through tyrosine kinases. C3G is activated by tyrosine phosphorylation and interaction with Crk adaptor proteins, whose expression is elevated in multiple human cancers. However, the molecular details of C3G activation and the interplay between phosphorylation and Crk interaction are poorly understood. [Methods]: We combined biochemical, biophysical, and cell biology approaches to elucidate the mechanisms of C3G activation. Binding of Crk adaptor proteins to four proline-rich motifs (P1 to P4) in C3G was characterized in vitro using isothermal titration calorimetry and sedimentation velocity, and in Jurkat and HEK293T cells by affinity pull-down assays. The nucleotide exchange activity of C3G over Rap1 was measured using nucleotide-dissociation kinetic assays. Jurkat cells were also used to analyze C3G translocation to the plasma membrane and the C3G-dependent activation of Rap1 upon ligation of T cell receptors. [Results]: CrkL interacts through its SH3N domain with sites P1 and P2 of inactive C3G in vitro and in Jurkat and HEK293T cells, and these sites are necessary to recruit C3G to the plasma membrane. However, direct stimulation of the GEF activity requires binding of Crk proteins to the P3 and P4 sites. P3 is occluded in resting C3G and is essential for activation, while P4 contributes secondarily towards complete stimulation. Tyrosine phosphorylation of C3G alone causes marginal activation. Instead, phosphorylation primes C3G lowering the concentration of Crk proteins required for activation and increasing the maximum activity. Unexpectedly, optimal activation also requires the interaction of CrkL-SH2 domain with phosphorylated C3G. [Conclusion]: Our study revealed that phosphorylation of C3G by Src and Crk-binding form a two-factor mechanism that ensures tight contr

Thermo-alterations in skeletal remains result from circumstances that can be key to understanding the context in which these appear. Here, we present the results of a series of experiments based on the exposure of animal remains to a range of different conditions and temperatures (up to 900°C) to document a variety of contexts that provide valuable information in fossil sites and forensic cases. Meat-bearing and defleshed remains (i.e. meat manually removed before the experiment) were exposed to high-temperatures, both directly or buried in different types of sediments (silt, sand, gravel and mixed sediment), in order to document colour changes and survival of soft tissues. Thus, our main goal was to monitor colour alteration and superficial modifications on the bone surface (i.e. cracks, as well as disarticulation of small mammal carcasses caused by high temperatures).

We propose an algorithm based on linear prediction that can perform both the lossless and near-lossless compression of RF signals. The proposed algorithm is coupled with two signal detection methods to determine the presence of relevant signals and apply varying levels of loss as needed. The first method uses spectrum sensing techniques, while the second one takes advantage of the error computed in each iteration of the Levinson–Durbin algorithm. These algorithms have been integrated as a new pre-processing stage into FAPEC, a data compressor first designed for space missions. We test the lossless algorithm using two different datasets. The first one was obtained from OPS-SAT, an ESA CubeSat, while the second one was obtained using a SDRplay RSPdx in Barcelona, Spain. The results show that our approach achieves compression ratios that are 23% better than gzip (on average) and very similar to those of FLAC, but at higher speeds. We also assess the performance of our signal detectors using the second dataset. We show that high ratios can be achieved thanks to the lossy compression of the segments without any relevant signal.

Despite the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway being frequently altered in T-ALL/LBL, no specific therapy has been approved for T-ALL/LBL patients with constitutive signalling by JAK/STAT, so there is an urgent need to identify pathway members that may be potential therapeutic targets. In the present study, we searched for JAK/STAT pathway members potentially modulated through aberrant methylation and identified SOCS3 hypermethylation as a recurrent event in T-ALL/LBL. Additionally, we explored the implications of SOCS3 deregulation in T-ALL/LBL and demonstrated that SOCS3 counteracts the constitutive activation of the JAK/STAT pathway through different molecular mechanisms. Therefore, SOCS3 emerges as a potential therapeutic target in T-ALL/LBL.

Abnormal N-methyl-D-aspartate receptor (NMDAr) function has been linked to oscillopathies, psychosis, and cognitive dysfunction in schizophrenia (SCZ). Here, we investigate the role of NMDAr hypofunction in pathological oscillations and behavior. We implanted mice with tetrodes in the dorsal/intermediate hippocampus and medial prefrontal cortex (mPFC), administered the NMDAr antagonist MK-801, and recorded oscillations during spontaneous exploration in an open field and in the y-maze spatial working memory test. Our results show that NMDAr blockade disrupted the correlation between oscillations and speed of movement, crucial for internal representations of distance. In the hippocampus, MK-801 increased gamma oscillations and disrupted theta/gamma coupling during spatial working memory. In the mPFC, MK-801 increased the power of theta and gamma, generated high-frequency oscillations (HFO 155–185 Hz), and disrupted theta/gamma coupling. Moreover, the performance of mice in the spatial working memory version of the y-maze was strongly correlated with CA1-PFC theta/gamma co-modulation. Thus, theta/gamma mediated by NMDAr function might explain several of SCZ’s cognitive symptoms and might be crucial to explaining hippocampal-PFC interaction.

El virus SARS-CoV-2 causa el COVID-19 al infectar las células a través de la interacción de la proteína de su espícula (S) con el receptor celular enzima convertidora de angiotensina 2 (ACE2). Para buscar inhibidores de este paso clave en la infección viral, examinamos una biblioteca interna (IQM-CSIC, Madrid) de compuestos multivalentes derivados de triptófano, primero usando pseudopartículas de Virus de Estomatits Vesicular que expresaban S (I2SysBio, UV y CSIC, Valencia), identificando un compuesto como potente inhibidor de entrada no citotóxico. La optimización química (IQM-CSIC) generó otros dos potentes inhibidores de entrada no citotóxicos que, como 2, también inhibieron la entrada celular de SARS-CoV-2 genuino (I2SysBio). Los estudios con proteínas recombinantes puras (IBV-CSIC, Valencia) usando termofluor y termoforesis de microescala revelaron la unión de estos compuestos a S, y a su dominio de unión al receptor producido separadamente, probando interferencia con la interacción con ACE2. La criomicroscopía electrónica de S (IBV-CSIC), libre o unido al compuesto activo, arrojó luz sobre los mecanismos de inhibición por estos compuestos de la entrada viral a la célula. Esta actividad triinstitucional combinada ha identificado y caracterizado una nueva clase de inhibidores de entrada de SARS-CoV-2 de claro potencial preventivo o terapéutico de COVID-19.

[Rationale],The present work shows comprehensive chromatographic methods and MS conditions that have been developed based on the chemical properties of each lipid subclass to detect low-abundance molecular species. This study shows that the developed methods can detect low- and/or very-low-abundant lipids like phosphatidic acid (PA) in the glycerophospholipid (GP) method; dihydroceramide (dhCer) and dihydrosphingosine/sphinganine (dhSPB) in the sphingolipid (SP) method; and lysophosphatidic acid (LPA), LPI, LPG and sphingosine-1-phosphate (SPBP) in the lysolipid method., [Methods], An optimised method for the extraction of lysolipids in plasma is used in addition to Folch extraction. Then, four chromatographic methods coupled with mass spectrometry using targeted and untargeted approaches are described here. Three of the methods use a tertiary pumping system to enable the inclusion of a gradient for analyte separation (pumps A and B) and an isocratic wash (pump C). This wash solution elutes interfering compounds that could cause background signal in the subsequent injections, reducing column lifetime., [Results], Semi-quantitative values for 37 lipid subclasses are reported for a plasma sample (NIST SRM 1950). Furthermore, the methods presented here enabled the identification of 338 different lipid molecular species for GPs (mono- and diacyl-phospholipds), SPs, sterols and glycerolipids. The methods have been validated, and the reproducibility is presented here., [Conclusions], The comprehensive analysis of the lipidome addressed here of glycerolipids, GPs, sterols and SPs is in good agreement with previously reported results, in the NIST SRM 1950 sample, by other laboratories. Ten lipid subclasses LPS, LPI, alkyl-lysophosphatidic acid/alkenyl-lysophosphatidic acid, alkyl-lysophosphatidylethanolamine/alkenyl-lysophosphatidylethanolamine, dhCer (d18:0), SPB (d18:1), dhSPB (d18:0) and SPBP (d18:2) have been detected using this comprehensive method and are uniquely reported here.

[EN] Acquiring immunocompetence is essential in the development of fish embryos, as they are exposed to environmental pathogens even before they are fertilized. Despite the importance of the antimicrobial function as the first line of defense against foreign microorganisms, little knowledge is available about its role in larval development. In vertebrates, transgenerational immune priming influences the acquisition of immunocompetence of specimens, regulating the selective allocation of nongenetic resources to their progeny and modulating their development. In this work, we primed teleost European sea bass broodstock females with a viral protein expression vector in order to evaluate the innate immunity development of their offspring. Several antimicrobial functions, the pattern of expression of gene coding for different antimicrobial peptides (AMPs), and their protein levels, were evaluated in eggs and larvae during development. Our data determined the presence of antimicrobial proteins of maternal origin in eggs, and that female vaccination increases antimicrobial activities and the transcription and synthesis of AMPs during larval development.

Vaccines against SARS-CoV-2 have been shown to be safe and effective but their protective efficacy against infection in the brain is yet unclear. Here, in the susceptible transgenic K18-hACE2 mouse model of severe coronavirus disease 2019 (COVID-19), we report a spatiotemporal description of SARS-CoV-2 infection and replication through the brain. SARS-CoV-2 brain replication occurs primarily in neurons, leading to neuronal loss, signs of glial activation and vascular damage in mice infected with SARS-CoV-2. One or two doses of a modified vaccinia virus Ankara (MVA) vector expressing the SARS-CoV-2 spike (S) protein (MVA-CoV2-S) conferred full protection against SARS-CoV-2 cerebral infection, preventing virus replication in all areas of the brain and its associated damage. This protection was maintained even after SARS-CoV-2 reinfection. These findings further support the use of MVA-CoV2-S as a promising vaccine candidate against SARS-CoV-2/COVID-19.

Pig slurries are widely used on calcareous soils in European rainfed systems. Here we assess their impact on the amount of soil organic carbon (SOC) and on the composition of humic- type substances (HTS). Seven doses of slurry (five from fattening pigs and two from sows) ranging from 1.0 to 4.8 Mg ha−1 yr−1 of or-ganic matter were evaluated after a period of 12 years and compared with mineral fertilizer treatment. At the end of the last annual cropping season (September), SOC was quantified, and HTS were isolated by alkaline extraction followed by acid precipitation, and studied by visible spectroscopy (800– 400 nm) and Fourier- transformed infrared spectroscopy (4000– 400 cm−1). Following the trend in the slurry organic matter applied rates, SOC increased from 9.5 g C kg−1 (min-eral treatment) to 13.8 g C kg−1. This SOC increase was equivalent to c. 25.4% of the slurry organic carbon applied. The incorporation of aliphatic structures, mainly polyalkyl, from slurries into the HTS tends to modify the composition of the soil organic matter (SOM), which is reflected in a decrease in the intensity of FT- IR peaks related to aromatic structures. Despite the trend of significant increase in SOC with fattening slurries, mainly from the organic matter rate of 1.6 Mg ha−1 yr−1 (c. 185 kg N ha−1), the composition of the HTS showed an impor-tant aliphatic enhancement. The FTIR results showed that using exclusively the relative intensities of specific peaks (alkyl, carboxyl, aromatic and amide groups) as variables for the discriminant analysis, it is possible to identify HA between different groups of soils treated with progressive levels of slurry. Although the new aliphatic components could be considered important to improve soil physi-cal quality, after the incorporation of additional SOM, the spectroscopic charac-teristics of HTS in soils treated with slurries suggested a weak effect in long- term C sequestration, as the newly incorporated OC forms are not qualitatively sim

Severe Acute Respiratory Syndrome Coronavirus 2 is the causative agent of Coronavirus Disease 2019 in humans. To date, little is known about the persistence of antibodies against SARS-CoV-2 in animals under natural conditions, in particular susceptible pets such as cat. This study reports the detection and monitoring of the humoral response against SARS-CoV-2 including the detection of immunoglobulins G specific for receptor binding domain of SARS-CoV-2 spike protein by an enzyme-linked immunosorbent assay and neutralizing antibodies by virus neutralization assay. Results showed that these antibodies last longer than 16 months in two naturally apparently healthy infected cats with the absence of clinicopathological findings during the follow-up. Moreover, re-infection is also possible with an important increase in virus neutralization test titers in both animals with no evident systemic signs found during each physical examination and with values of hematologic and biochemical parameters inside the normal reference intervals. Our results confirm a slow but progressive decrease of the kinetics and immunity of neutralizing antibodies in cats after the infection. Furthermore, similar to humans SARS-CoV-2 reinfection can stimulate an increase of the neutralizing antibodies determined by these two serological techniques in domestic cats.

La composición volátil de la uva es uno de los parámetros más importantes para determinar la calidad del mosto y del vino. Los aromas de la uva, también llamados primarios, se dividen en aromas varietales y prefermentativos. Estos compuestos se encuentran en muy bajas concentraciones en la uva, por lo que, para llevar a cabo su identificación y cuantificación, se requiere de un método eficaz de extracción para su posterior análisis cromatográfico. El análisis de compuestos volátiles de las uvas mediante métodos cromatográficos presenta numerosos inconvenientes, como el consumo de tiempo, la pérdida de muestra y preparación de la misma, los costes de reactivos e instrumentación y la necesidad de personal formado, por lo que estos equipos solo están disponibles en algunos centros de investigación y en grandes bodegas. Actualmente no existe ningún método que permita realizar análisis rutinarios a tiempo real de la composición aromática de las uvas a lo largo de su maduración, hecho que le permitiría al viticultor tomar decisiones respecto a las prácticas vitícolas, a la elección de la fecha de vendimia o a la clasificación de la uva en función de su calidad aromática. Este hecho ha cobrado mayor importancia en los últimos años debido al desequilibrio entre la madurez industrial (contenido de azúcares/ácidos) y las madureces fenólica y aromática en la uva, provocado por el efecto del cambio climático. Como consecuencia del mismo, las bayas alcanzan más rápidamente el contenido adecuado de azúcares (medidos como sólidos solubles totales (TSS, Total Soluble Solids) (ºBrix)), pero no de compuestos fenólicos y aromáticos (compuestos que se sintetizan más tarde en la baya). En los últimos años se han desarrollado métodos rápidos y no destructivos que permiten relacionar datos espectrales con la concentración de componentes químicos específicos (TSS, compuestos fenólicos, compuestos aromáticos, compuestos nitrogenados…). Dos de estas tecnologías son la espectroscopía de infra, Para ello, en primer lugar, se optimizaron tres técnicas para la extracción de compuestos volátiles en mosto: extracción mediante barrita agitadora absorbente (SBSE, Stir Bar Sorptive Extraction), su variante multi-SBSE (mSBSE), en la que se utilizaron barritas agitadoras de polidimetilsiloxano (PDMS) y de etilenglicol (EG) de forma simultánea, y microextracción en fase sólida mediante película fina (TF-SPME, Thin Film – Solid Phase Microextraction), en la que se probaron las películas finas de PDMS/carboxen (PDMS/CAR) y de PDMS/divinilbenceno (PDMS/DVB). Los factores optimizados fueron el modo, velocidad, tiempo y temperatura de extracción, y la adición de NaCl. A su vez, se puso a punto el análisis de dichos compuestos por cromatografía de gases-espectrometría de masas (GC-MS, Gas Chromatography – Mass Spectrometry). Una vez optimizadas las tres técnicas, se eligió la que mejores resultados proporcionó, que fue TF-SPME-GC-MS, con la película fina de PDMS/CAR y bajo las condiciones de inmersión directa (DI), a 500 rpm, durante 6 horas a 20 ⁰C. Dicha técnica se utilizó posteriormente como método de referencia para la determinación de compuestos volátiles en las muestras de mosto. En segundo lugar, se tomaron medidas espectrales, en condiciones de laboratorio, de 240 muestras de Vitis vinifera L. Tempranillo y 240 de Tempranillo Blanco, recogidas durante los años 2019 y 2020, mediante HSI en el rango 400-1.000 nm y mediante NIRS en el rango 1.100 – 2.100 nm. En tercer lugar, se midieron los TSS y se analizaron los compuestos volátiles de esas mismas muestras con el método TF-SPME-GC-MS optimizado, se integraron los cromatogramas y se obtuvieron, de esta forma, los datos de referencia. Por último, se construyeron los modelos de calibración multivariante, mediante regresión por mínimos cuadrados parciales modificados (MPLS), utilizando los datos espectrales adquiridos y los datos de referencia. Los resultados obtenidos demostraron que las técnicas HSI y NIRS permiten d

Habitat use is a virtually universal activity among animals and is highly relevant as regards designing wildlife management and conservation actions. This has led to the development of a great variety of methods to study it, of which resource selection functions combined with biologging-derived data (RSF) is the most widely used for this purpose. However this approach has some constraints, such as its invasiveness and high costs. Analytical approaches taking into consideration imperfect detection coupled with camera trap data (IDM) have, therefore, emerged as a non-invasive cost-effective alternative. However, despite the fact that both approaches (RSF and IDM) have been used in habitat selection studies, they should also be comparatively assessed. The objective of this work is consequently to assess them from two perspectives: explanatory and predictive. This has been done by analyzing data obtained from camera traps (60 sampling sites) and biologging (17 animals monitored: 7 red deer Cervus elaphus, 6 fallow deer Dama dama and 4 wild boar Sus scrofa) in the same periods using IDM and RSF, respectively, in Doñana National Park (southern Spain) in order to explain and predict habitat use patterns for three studied species. Our results showed discrepancies between the two approaches, as they identified different predictors as being the most relevant to determine species intensity of use, and they predicted spatial patterns of habitat use with a contrasted level of concordance, depending on species and scale. Given these results and the characteristics of each approach, we suggested that although partly comparable interpretations can be obtained with both approaches, they are not equivalent but rather complementary. The combination of data from biologging and camera traps would, therefore, appear to be suitable for the development of an analytical framework with which to describe and characterise the habitat use processes of wildlife.

[Background and Aims]: The molecular mechanisms driving non-alcoholic fatty liver disease (NAFLD) are poorly understood; however, microRNAs might play a key role in these processes. We hypothesize that let-7d- 5p could contribute to the pathophysiol-ogy of NAFLD and serve as a potential diagnostic biomarker., [Methods]: We evaluated let-7d- 5p levels and its targets in liver biopsies from a cross- sectional study including patients with NAFLD and healthy donors, and from a mouse model of NAFLD. Moreover, the induction of let-7d- 5p expression by fatty acids was evaluated in vitro. Further, we overexpressed let-7d- 5p in vitro to corroborate the results observed in vivo. Circulating let-7d- 5p and its potential as a NAFLD biomarker was determined in isolated extracellular vesicles from human plasma by RT-qPCR., [Results]: Our results demonstrate that hepatic let-7d-5p was significantly up-regulated in patients with steatosis, and this increase correlated with obesity and a decreased expression of AKT serine/threonine kinase (AKT), insulin-like growth factor 1 (IGF1), IGF-I receptor (IGF1R) and insulin receptor (INSR). These alterations were corroborated in a NAFLD mouse model. In vitro, fatty acids increased let-7d-5p expression, and its overexpression decreased AKT, IGF-IR and IR protein expression. Furthermore, let-7d-5p hindered AKT phosphorylation in vitro after insulin stimulation. Finally, circulating let-7d-5p significantly decreased in steatosis patients and receiver operating characteristic (ROC) analyses confirmed its utility as a diagnostic biomarker., [Conclusions]: Our results highlight the emerging role of let-7d-5p as a potential therapeutic target for NAFLD since its overexpression impairs hepatic insulin signalling, and also, as a novel non-invasive biomarker for NAFLD diagnosis.

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Upon the emergence of SARS-CoV-2 in the human population, it was conjectured that for this coronavirus the dynamic intra-host heterogeneity typical of RNA viruses would be toned down. Nothing of this sort is observed. Here we review the main observations on the complexity and diverse composition of SARS-CoV-2 mutant spectra sampled from infected patients, within the framework of quasispecies dynamics. The analyses suggest that the information provided by myriads of genomic sequences within infected individuals may have a predictive value of the genomic sequences that acquire epidemiological relevance. Possibilities to reconcile the presence of broad mutant spectra in the large RNA coronavirus genome with its encoding a 3' to 5' exonuclease proofreading-repair activity are considered. Indeterminations in the behavior of individual viral genomes provide a benefit for the survival of the ensemble. We propose that this concept falls in the domain of "stochastic thinking," a notion that applies also to cellular processes, as a means for biological systems to face unexpected needs.

The hippocampus hosts the continuous addition of new neurons throughout life—a phenomenon named adult hippocampal neurogenesis (AHN). Here we revisit the occurrence of AHN in more than 110 mammalian species, including humans, and discuss the further validation of these data by single-cell RNAseq and other alternative techniques. In this regard, our recent studies have addressed the long-standing controversy in the field, namely whether cells positive for AHN markers are present in the adult human dentate gyrus (DG). Here we review how we developed a tightly controlled methodology, based on the use of high-quality brain samples (characterized by short postmortem delays and ≤24 h of fixation in freshly prepared 4% paraformaldehyde), to address human AHN. We review that the detection of AHN markers in samples fixed for 24 h required mild antigen retrieval and chemical elimination of autofluorescence. However, these steps were not necessary for samples subjected to shorter fixation periods. Moreover, the detection of labile epitopes (such as Nestin) in the human hippocampus required the use of mild detergents. The application of this strictly controlled methodology allowed reconstruction of the entire AHN process, thus revealing the presence of neural stem cells, proliferative progenitors, neuroblasts, and immature neurons at distinct stages of differentiation in the human DG. The data reviewed here demonstrate that methodology is of utmost importance when studying AHN by means of distinct techniques across the phylogenetic scale. In this regard, we summarize the major findings made by our group that emphasize that overlooking fundamental technical principles might have consequences for any given research field.

La aparición de nuevas enfermedades causadas por bacterias resistentes a los tratamientos con antibióticos constituye un problema de talla mundial que afecta la salud humana, la sanidad de los animales, la ganadería, la agricultura, el comercio y por ende la economía mundial. Esta resistencia a los antibióticos se debe a diferentes factores, pero el uso indiscriminado e inapropiado de estos medicamentos es uno de los factores que más contribuye a la aparición de este fenómeno que causa un gran impacto clínico, epidemiológico y microbiológico. En el plan nacional de España frente a la resistencia a los antibióticos 2019-2021 desarrollado por el ministerio de sanidad, consumo y bienestar social y la agencia española de medicamentos y productos sanitarios (Plan Nacional frente a la Resistencia a los Antibióticos (PRAN) 2019-2021, s. f.) reportaron: que en toda Europa 35.000 personas mueren cada año a causa de las infecciones hospitalarias producidas por bacterias resistentes; y de acuerdo con los datos del registro del Conjunto Mínimo Básico de Datos (CMBD), en España alrededor de 4000 personas mueren al año por la misma causa. Si no se toman medidas de carácter urgente se estima que en 35 años las muertes en Europa por infecciones multirresistentes ascenderán 390000 casos al año y en España a 40000 muertes anuales, además la resistencia desbancará a el cáncer como primera causa de muerte. Frente a esta premisa, existen varias estrategias para abordar esta problemática; vigilancia, control, prevención, investigación, formación y comunicación. En general a nivel de investigación se busca identificar y desarrollar nuevos antibióticos e incrementar el conocimiento sobre el problema de la resistencia. Una de las líneas de estudio en nuestro grupo de investigación se basa en estudiar distintos reguladores generales de la producción de antibióticos entre los que se encuentran los TCSs y los sistemas XRE/DUF397. Los sistemas XRE/DUF397 han sido propuestos por otros autores co

The use of metal–organic frameworks (MOFs) as templates or precursors in the manufacture of heterogeneous catalysts is highly attractive due to the transfer of MOFs’ inherent porosity and homogeneous metallic distribution to the derived structure. Herein, we report on the preparation of MOF-derived Ru@ZrO2 catalysts by controlled thermal treatment of zirconium-based MOF UiO-66 with ruthenium moieties. Ru3+ (3 or 10 mol%) precursor was added to UiO-66 synthesis and, subsequently, the as-synthesized hybrid structure was calcined in flowing air at different temperatures (400–600 °C) to obtain ZrO2-derived oxides doped with highly dispersed Ru metallic clusters. The materials were tested for the catalytic photo-thermal conversion of CO2 to CH4. Methanation experiments were conducted in a continuous flow (feed flow rate of 5 sccm and 1:4 CO2 to H2 molar ratio) reactor at temperatures from 80 to 300 °C. Ru0.10@ZrO2 catalyst calcined at 600 °C was able to hydrogenate CO2 to CH4 with production rates up to 65 mmolCH4·gcat.–1·h–1, CH4 yield of 80% and nearly 100% selectivity at 300 °C. The effect of the illumination was investigated with this catalyst using a high-power visible LED. A CO2 conversion enhancement from 18% to 38% was measured when 24 sun of visible LED radiation was applied, mainly due to the increase in the temperature as a result of the efficient absorption of the radiation received. MOF-derived Ru@ZrO2 catalysts have resulted to be noticeably active materials for the photo-thermal hydrogenation of CO2 for the purpose of the production of carbon-neutral methane. A remarkable effect of the ZrO2 crystalline phase on the CH4 selectivity has been found, with monoclinic zirconia being much more selective to CH4 than its cubic allotrope.

Thinning treatments along with the establishment of mixed forest stands have been put forward as possible adaptation strategies to cope with climate change, although the effectiveness of combining these two measures has scarcely been studied and may vary depending on stand conditions and the thinning regime employed. The aim of this study was to better understand the effect of commercial thinning and of the different growth behavior of two coexisting species on their inter- and intra-annual cumulative radial increment patterns. For this purpose, we studied radial increment in a Scots pine-Pyrenean oak (Pinus sylvestris L.-Quercus pyrenaica Willd.) Mediterranean mixed forest in north-west Spain over two climatically contrasting years (2016–2017). The data came from a thinning trial consisting of a randomized latin square design with a control and two commercial thinning treatments from below; one moderate and the other heavy, removing 25% and 50 % of initial basal area, respectively, of both species. The radial increment was analyzed based on bi-weekly readings from band dendrometers installed on 90 oak and pine trees. A non-linear mixed model based on double-Richards curve was fitted to explore the differences between thinning treatments and species response in the intra-annual cumulative radial increment patterns. Inter-annual basal area increments for each species at stand level were quantified by aggregating the tree estimates obtained from the model fitted in the first step. Tree and stand level growth were greater in Scots pine, which also showed a greater growth response to early spring droughts than the Pyrenean oak. Heavy thinning increased radial increment in trees of both species at the expense of decreased total stand basal area. At species level, basal area growth in Scots pine decreased through thinning, whereas for Pyrenean oak, the heavy thinning intensity resulted in the same basal area growth as the control. Thus, heavy thinning induced a trade-off

Understanding the triggering mechanisms of induced seismicity remains one of the most critical challenges in geo-energy applications. This Thesis aims at assessing (1) fault stability and induced seismicity potential under various geological settings in the framework of poromechanics, and (2) poromechanical effects on the earthquake nucleation process. We propose two closed-form solutions for poromechanical stress and displacement due to pore pressure changes in the reservoir with the inclusion theory and Green’s function. The solutions are valid for various fault offsets, dip angles, reservoir lengths, and permeable and impermeable faults. Induced seismicity potential of impermeable faults is always larger than that of permeable faults. Ground displacement increases with fault dip and decreases with increasing fault offset, in contrast, reservoir geometry shows a stronger effect than fault geometry. Applying the analytical solutions to the Pohang Mw 5.5 earthquake achieves both deterministic and stochastic poromechanical analyses, providing a consistent triggering mechanism of the mainshock. Results also show that a small overpressure can trigger a damaging earthquake when preexisting faults are initially critically stressed. Incorporating the analytical stress solution into the interfacial slip model reveals that including poroelasticity drastically affects the nucleation process, finding new slip regimes and reducing the magnitude of induced seismicity in some regimes. Analyzing the slip regime map and earthquake magnitude map finds the favorable and unfavorable conditions as a function of rock properties, background stress, and injection parameters for deploying geo-energy projects. Neglecting poroelastic effects cannot recognize many of such conditions.

The interaction between the plant lipid transfer protein Pru p 3 and phytosphingosine was assessed using an atomic force microscope. Phytosphingosine was covalently immobilized on DeepTipTM probes and Pru p 3 on MicroDeckTM functionalized substrates. Single-molecular interaction events between both molecules were retrieved and classified and the distribution for each one of the identified types was calculated. A success rate of over 70% was found by comparing the number of specific Pru p 3-phytosphingosine interaction events with the total number of recorded curves. The analysis of the distribution established among the various types of curves was further pursued to distinguish between those curves that can mainly be used for assessing the recognition between phytosphingosine (sensor molecule) and Pru p 3 (target molecule) in the context of affinity atomic force microscopy, and those that entail details of the interaction and might be employed in the context of force spectroscopy. The successful application of these functionalized probes and substrates to the characterization of the low-intensity hydrophobic interaction characteristic of this system is a clear indication of the potential of exploiting this approach with an extremely wide range of different biological molecules of interest. The possibility of characterizing molecular assembly events with single-molecule resolution offers an advantageous procedure to plough into the field of molecular biomimetics.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic. The severity of COVID-19 increases with each decade of life, a phenomenon that suggest that organismal aging contributes to the fatality of the disease. In this regard, we and others have previously shown that COVID-19 severity correlates with shorter telomeres, a molecular determinant of aging, in patient’s leukocytes. Lung injury is a predominant feature of acute SARS-CoV-2 infection that can further progress to lung fibrosis in post-COVID-19 patients. Short or dysfunctional telomeres in Alveolar type II (ATII) cells are sufficient to induce pulmonary fibrosis in mouse and humans. Here, we analyze telomere length and the histopathology of lung biopsies from a cohort of alive post-COVID-19 patients and a cohort of age-matched controls with lung cancer. We found loss of ATII cellularity and shorter telomeres in ATII cells concomitant with a marked increase in fibrotic lung parenchyma remodeling in post- COVID-19 patients compared to controls. These findings reveal a link between presence of short telomeres in ATII cells and long-term lung fibrosis sequel in Post-COVID-19 patients.

Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N7-methylguanosine (m7G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m7G tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5'tRNA fragments. 5'tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m7G tRNA methylation in cancer cell translation control and tumour biology.

B-cell acute lymphoblastic leukemia (B-ALL) stands as the primary contributor to childhood cancer-related mortality on a global scale. The development of the most conventional forms of this disease has been proposed to be conducted by two different steps influenced by different types of risk factors. The first step is led by a genetic insult that is presumably acquired before birth that transforms a healthy cell into a preleukemic one, which is maintained untransformed until the second step takes place. This necessary next step to leukemia development will be triggered by different risk factors to which children are exposed after birth. Murine models that recap the stepwise progression of B-ALL have been instrumental in identifying environmental and genetic factors that contribute to disease risk. Recent evidence from these models has demonstrated that specific environmental risk factors, such as common infections or gut microbiome dysbiosis, induce immune stress, driving the transformation of preleukemic cells, and harboring genetic alterations, into fully transformed leukemic cells. Such models serve as valuable tools for investigating the mechanisms underlying preleukemic events and can aid in the development of preventive approaches for leukemia in child. Here, we discuss the existing knowledge, learned from mouse models, of the impact of genetic and environmental risk factors on childhood B-ALL evolution and how B-ALL prevention could be reached by interfering with preleukemic cells.

Human cancers comprise an heterogeneous array of diseases with different progression patterns and responses to therapy. However, they all develop within a host context that constrains their natural history. Since it occurs across the diversity of organisms, one can conjecture that there is order in the cancer multiverse. Is there a way to capture the broad range of tumor types within a space of the possible? Here we define the oncospace, a coordinate system that integrates the ecological, evolutionary and developmental components of cancer complexity. The spatial position of a tumor results from its departure from the healthy tissue along these three axes, and progression trajectories inform about the components driving malignancy across cancer subtypes. We postulate that the oncospace topology encodes new information regarding tumorigenic pathways, subtype prognosis, and therapeutic opportunities: treatment design could benefit from considering how to nudge tumors toward empty evolutionary dead ends in the oncospace.