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The 23rd FEBS YSF was held from 26th to 29th June 2024 in Pavia, Italy. Over 100 PhD students and early postdoctoral researchers from around 30 different countries came together at the inspiring rooms of the University of Pavia for a four‐day event. This year's topic was ‘Biochemistry for bridging the gap’, meaning the opportunity to have a comprehensive perspective on all biochemistry applications. Four renowned keynote speakers presented their latest research, accompanied by four career‐focused speakers, as well as additional sessions on academic career opportunities, including fellowships, women in science, and laboratory sustainability. Additionally, 10 selected YSF participants gave short talks to a large audience, while the remaining attendees shared their research findings through flash talks and two dedicated poster sessions. Scientific exchange and networking were encouraged during the poster sessions, breaks, and the social events. The meeting was a prelude before attending the 48th FEBS congress, celebrated in Milan. The success of the series will be continued during the 24th YSF edition: ‘Inspired by nature, driven by science’, which will take place from 2nd to 5th July 2025 in Sapanca, Türkiye.

Abstract Translation is regulated mainly in the initiation step, and its dysregulation is implicated in many human diseases. Several proteins have been found to regulate translational initiation, including Pdcd4 (programmed cell death gene 4). Pdcd4 is a tumor suppressor protein that prevents cell growth, invasion, and metastasis. It is downregulated in most tumor cells, while global translation in the cell is upregulated. To understand the mechanisms underlying translational control by Pdcd4, we used single-particle cryo-electron microscopy to determine the structure of human Pdcd4 bound to 40S small ribosomal subunit, including Pdcd4-40S and Pdcd4-40S-eIF4A-eIF3-eIF1 complexes. The structures reveal the binding site of Pdcd4 at the mRNA entry site in the 40S, where the C-terminal domain (CTD) interacts with eIF4A at the mRNA entry site, while the N-terminal domain (NTD) is inserted into the mRNA channel and decoding site. The structures, together with quantitative binding and in vitro translation assays, shed light on the critical role of the NTD for the recruitment of Pdcd4 to the ribosomal complex and suggest a model whereby Pdcd4 blocks the eIF4F-independent role of eIF4A during recruitment and scanning of the 5′ UTR of mRNA.

Abstract The advancement of technologies and the development of more efficient artificial intelligence (AI) enable the processing of large amounts of data in a very short time. Concurrently, the increase in information within biological databases, such as 3D molecular structures or networks of functional macromolecule associations, will facilitate the creation of new methods for risk assessment that can serve as alternatives to animal testing. Specifically, the predictive capabilities of AI as new approach methodologies (NAMs) are poised to revolutionise risk assessment approaches. Our previous studies on molecular docking predictions, using the software Autodock Vina, indicated high‐affinity binding of certain toxic chemicals to the 3D structures of human proteins associated with nervous and reproductive functions. Similar approaches revealed potential sublethal interactions of neonicotinoids with proteins linked to the bees' immune system. Building on these findings, we plan to develop an AI‐based decision tool that exploits the data available on the toxicity of the most know chemical, such as LD50, and the data obtainable by their interaction with the human proteins to support risk assessment studies for multiple stressors still not characterised. Our focus will be on utilising these new bioinformatics methodologies to develop specific experimental designs that allow for confident and predictable study of the toxic and sublethal effects of pesticides on humans. We will also validate the developed NAMs by integrating existing in vivo information from scientific literature and technical reports. These approaches will significantly impact toxicity studies, guiding researchers' experiments and greatly reducing the need for animal testing.

Summary: CombiVacS study has demonstrated a strong immune response of the heterologous ChAdOx1-S/BNT162b2 vaccine combination. The primary outcomes of the study were to assess the humoral immune response against SARS-CoV-2, 28 days after a third dose of a mRNA vaccine, in subjects that received a previous prime-boost scheme with ChAdOx1-S/BNT162b2. Secondary outcomes extended the study to 3 and 6 months. The third vaccine dose of mRNA-1273 in naive participants previously vaccinated with ChAdOx1-S/BNT162b2 regimen reached higher neutralizing antibodies titers against the variants of concern Delta and BA.1 lineage of Omicron compared with those receiving a third dose of BNT162b2 at day 28. These differences between BNT162b2 and mRNA-1273 arms were observed against the ancestral variant G614 at day 90. Suboptimal neutralizing response was observed against BQ.1.1, XBB.1.5/XBB.1.9, and JN.1 in a relevant proportion of individuals 180 days after the third dose, even after asymptomatic Omicron breakthrough infections. EudraCT (2021-001978-37); ClinicalTrials.gov (NCT04860739).

The encapsulation of phase change materials (PCMs) into additive manufactured porous supports is attracting great interest for developing thermal energy storage (TES) materials with improved energy performance. Here, highly porous (86 %) self-supported 3D activated carbon/alumina supports are fabricated by direct ink writing (DIW) and, then, infiltrated with solar salt, a highly corrosive PCM with a melting temperature around 220 °C commonly employed in concentrated solar power plants. This novel, robust, chemically compatible, and lightweight infiltrated 3DTES exhibits good thermal energy storage efficiency (70 %) and thermal stability, high energy storage density (381 J g−1), and avoids the liquid leakage of the molten salt. Besides, the 3D activated carbon/alumina support promotes a better ability to absorb solar energy (79 %) and enhances the thermal conductivity of the solar salt (up to 64 %). These results validate the use of DIW for manufacturing innovative TES with an enhanced energy storage behaviour.

Summary: Compartmentalization of proteins by liquid-liquid phase separation (LLPS) is used by cells to control biochemical reactions spatially and temporally. Among them, the recruitment of proteins to DNA foci and nucleolar trafficking occur by biomolecular condensation. Within this frame, the oncoprotein SET/TAF-Iβ plays a key role in both chromatin remodeling and DNA damage response, as does nucleophosmin (NPM1) which indeed participates in nucleolar ribosome synthesis. Whereas phase separation by NPM1 is widely characterized, little is known about that undergone by SET/TAF-Iβ. Here, we show that SET/TAF-Iβ experiences phase separation together with respiratory cytochrome c (Cc), which translocates to the nucleus upon DNA damage. Here we report the molecular mechanisms governing Cc-induced phase separation of SET/TAF-Iβ and NPM1, where two lysine-rich clusters of Cc are essential to recognize molecular surfaces on both partners in a specific and coordinated manner. Cc thus emerges as a small, globular protein with sequence-encoded heterotypic phase-separation properties.

Summary: The posttranslational modification of proteins critically influences many biological processes and is a key mechanism that regulates the function of the RNA-binding protein Hu antigen R (HuR), a hub in liver cancer. Here, we show that HuR is SUMOylated in the tumor sections of patients with hepatocellular carcinoma in contrast to the surrounding tissue, as well as in human cell line and mouse models of the disease. SUMOylation of HuR promotes major cancer hallmarks, namely proliferation and invasion, whereas the absence of HuR SUMOylation results in a senescent phenotype with dysfunctional mitochondria and endoplasmic reticulum. Mechanistically, SUMOylation induces a structural rearrangement of the RNA recognition motifs that modulates HuR binding affinity to its target RNAs, further modifying the transcriptomic profile toward hepatic tumor progression. Overall, SUMOylation constitutes a mechanism of HuR regulation that could be potentially exploited as a therapeutic strategy for liver cancer.

Abstract Skeletal muscle is more resilient to ischemia-reperfusion injury than other organs. Tissue specific post-translational modifications of cytochrome c (Cytc) are involved in ischemia-reperfusion injury by regulating mitochondrial respiration and apoptosis. Here, we describe an acetylation site of Cytc, lysine 39 (K39), which was mapped in ischemic porcine skeletal muscle and removed by sirtuin5 in vitro. Using purified protein and cellular double knockout models, we show that K39 acetylation and acetylmimetic K39Q replacement increases cytochrome c oxidase (COX) activity and ROS scavenging while inhibiting apoptosis via decreased binding to Apaf-1, caspase cleavage and activity, and cardiolipin peroxidase activity. These results are discussed with X-ray crystallography structures of K39 acetylated (1.50 Å) and acetylmimetic K39Q Cytc (1.36 Å) and NMR dynamics. We propose that K39 acetylation is an adaptive response that controls electron transport chain flux, allowing skeletal muscle to meet heightened energy demand while simultaneously providing the tissue with robust resilience to ischemia-reperfusion injury.

Abstract Obesity is associated with adipose tissue dysfunction through the differentiation and expansion of pre-adipocytes to adipocytes (hyperplasia) and/or increases in size of pre-existing adipocytes (hypertrophy). A cascade of transcriptional events coordinates the differentiation of pre-adipocytes into fully differentiated adipocytes; the process of adipogenesis. Although nicotinamide N-methyltransferase (NNMT) has been associated with obesity, how NNMT is regulated during adipogenesis, and the underlying regulatory mechanisms, remain undefined. In present study we used genetic and pharmacological approaches to elucidate the molecular signals driving NNMT activation and its role during adipogenesis. Firstly, we demonstrated that during the early phase of adipocyte differentiation NNMT is transactivated by CCAAT/Enhancer Binding Protein beta (CEBPB) in response to glucocorticoid (GC) induction. We found that Nnmt knockout, using CRISPR/Cas9 approach, impaired terminal adipogenesis by influencing the timing of cellular commitment and cell cycle exit during mitotic clonal expansion, as demonstrated by cell cycle analysis and RNA sequencing experiments. Biochemical and computational methods showed that a novel small molecule, called CC-410, stably binds to and highly specifically inhibits NNMT. CC-410 was, therefore, used to modulate protein activity during pre-adipocyte differentiation stages, demonstrating that, in line with the genetic approach, chemical inhibition of NNMT at the early stages of adipogenesis impairs terminal differentiation by deregulating the GC network. These congruent results conclusively demonstrate that NNMT is a key component of the GC-CEBP axis during the early stages of adipogenesis and could be a potential therapeutic target for both early-onset obesity and glucocorticoid-induced obesity.

Common variable immunodeficiency (CVID) is the most common symptomatic immunodeficiency in adults. It comprises a group of syndromes whose etiology involves genetic, epigenetic, microbiota, and environmental factors. We present the case of a 46-year-old Caucasian male patient with CVID and an immune dysregulation phenotype. The particular elements of the case consisted of an atypical clinical course, which undoubtedly demonstrates the great variability of clinical manifestations that these types of patients can suffer from, including bacterial and viral infections, autoimmune phenomena, and neoplasia. Notably, the patient suffered from recurrent gastrointestinal infection with macrolide-resistant Campylobacter jejuni and gastroduodenal disease and viraemia by cytomegalovirus (CMV). In addition, CMV was postulated as the main pro-oncogenic factor contributing to the development of early-onset intestinal-type gastric adenocarcinoma, for which the patient underwent gastrectomy. The patient’s evolution was difficult, but finally, as a result of the multidisciplinary approach, clinical stabilization and improvement in his quality of life were achieved. Based on our brief literature review, this is the first reported case of this clinical complexity. Our experience could help with the management of future patients with CVID and may also update current epidemiological data on CVID.

Electron transfer between mitochondrial cytochrome c and subunit of cytochrome bc 1 can proceed at long distance. Here the authors investigate further the mechanism and show phosphorylation regulation of the interactions between the protein partners in the electron transport chain.

Abstract Chromatin homeostasis mediates essential processes in eukaryotes, where histone chaperones have emerged as major regulatory factors during DNA replication, repair, and transcription. The dynamic nature of these processes, however, has severely impeded their characterization at the molecular level. Here, fluorescence optical tweezers are applied to follow histone chaperone dynamics in real time. The molecular action of SET/template‐activating factor‐Iβ and nucleophosmin 1—representing the two most common histone chaperone folds—are examined using both nucleosomes and isolated histones. It is shown that these chaperones present binding specificity for fully dismantled nucleosomes and are able to recognize and disrupt non‐native histone‐DNA interactions. Furthermore, the histone eviction process and its modulation by cytochrome c are scrutinized. This approach shows that despite the different structures of these chaperones, they present conserved modes of action mediating nucleosome remodeling.

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

Intrinsic protein flexibility is of overwhelming relevance for intermolecular recognition and adaptability of highly dynamic ensemble of complexes, and the phenomenon is essential for the understanding of numerous biological processes. These conformational ensembles—encounter complexes—lack a unique organization, which prevents the determination of well-defined high resolution structures. This is the case for complexes involving the oncoprotein SET/template-activating factor-Iβ (SET/TAF-Iβ), a histone chaperone whose functions and interactions are significantly affected by its intrinsic structural plasticity. Besides its role in chromatin remodeling, SET/TAF-Iβ is an inhibitor of protein phosphatase 2A (PP2A), which is a key phosphatase counteracting transcription and signaling events controlling the activity of DNA damage response (DDR) mediators. During DDR, SET/TAF-Iβ is sequestered by cytochrome c (Cc) upon migration of the hemeprotein from mitochondria to the cell nucleus. Here, we report that the nuclear SET/TAF-Iβ:Cc polyconformational ensemble is able to activate PP2A. In particular, the N-end folded, globular region of SET/TAF-Iβ (a.k.a. SET/TAF-Iβ ΔC)—which exhibits an unexpected, intrinsically highly dynamic behavior—is sufficient to be recognized by Cc in a diffuse encounter manner. Cc-mediated blocking of PP2A inhibition is deciphered using an integrated structural and computational approach, combining small-angle X-ray scattering, electron paramagnetic resonance, nuclear magnetic resonance, calorimetry and molecular dynamics simulations.

Abstract Post‐translational modifications frequently modulate protein functions. Lysine acetylation in particular plays a key role in interactions between respiratory cytochrome c and its metabolic partners. To date, in vivo acetylation of lysines at positions 8 and 53 has specifically been identified in mammalian cytochrome c, but little is known about the structural basis of acetylation‐induced functional changes. Here, we independently replaced these two residues in recombinant human cytochrome c with glutamine to mimic lysine acetylation and then characterized the structure and function of the resulting K8Q and K53Q mutants. We found that the physicochemical features were mostly unchanged in the two acetyl‐mimetic mutants, but their thermal stability was significantly altered. NMR chemical shift perturbations of the backbone amide resonances revealed local structural changes, and the thermodynamics and kinetics of electron transfer in mutants immobilized on gold electrodes showed an increase in both protein dynamics and solvent involvement in the redox process. We also observed that the K8Q (but not the K53Q) mutation slightly increased the binding affinity of cytochrome c to its physiological electron donor, cytochrome c1—which is a component of mitochondrial complex III, or cytochrome bc1—thus suggesting that Lys8 (but not Lys53) is located in the interaction area. Finally, the K8Q and K53Q mutants exhibited reduced efficiency as electron donors to complex IV, or cytochrome c oxidase.

Mediante una selección de extractos de testimonios orales, recogidos desde la década de los noventa del pasado siglo XX y hasta la actualidad, este artículo reconsidera las ideas sobre la nostalgia en el contexto del proceso de desindustrialización y transformación posindustrial en las cuencas mineras de Asturias. A partir de la idea de la persistencia del desindustrialismo, conceptuado como “Thehalf- life of deindustrialization” por la investigadora Sherry Linkon, se busca trasladar cómo las narrativas, discursos y representaciones sobre ese proceso movilizan simbólicamente el pasado industrial para encontrar respuestas ante las incertidumbres del presente, sin que ello necesariamente implique adolecer de lo que se ha etiquetado como el “mal” de la nostalgia. Del mismo modo, estas narrativas pueden ser vistas como representación de la existencia de una estructura de sentimiento.

Background: The impact of the COVID-19 on the well-being of people with intellectual disabilities (PID) has been little studied. Methods: We analyzed its impact with a cohort study quantitatively analyzing anxiety, depression, organic symptoms, quality of life, and support needs in 24 PID, aged 19–74 years (x¯ 40, σ = 13.09), living in a residential center, before, during, and after the pandemic. Results: Their mental health improved unexpectedly at the onset of the lockdown although there was an increase in organic symptoms. But, with the progress of the lockdown, their mental health deteriorated drastically. On the contrary, as expected, their quality of life and support needs worsened from the beginning of the lockdown until the country returned to normality, a time when there was a general recovery, without reaching pre-pandemic levels. These results show that the mental health of PID was affected differently to that of people without intellectual disabilities.

Background: Despite progresses in autoimmune encephalitis and related disorders (AERD), they remain a major challenge in daily clinical practice. Objectives: To describe a tertiary hospital's longitudinal experience in AERD between 2005 and 2020. Methods: Single-centre retrospective analysis of 43 patients. Results: 43 patients were included, 55.8% with positive antibodies (10 antiGAD, 4 antiNMDAR, 2 antiGABABR, 2 antiLGI1, 2 antiCASPR2, 1 antiIgLON5, 1 antiHu, 1 antiYo, 1 antiCV2 and 1 antiMa2, detecting coexisting antibodies in one patient: antiNMDAR+antiGABABR); 28% with negative antibodies; and 16.2% with steroid responsive encephalitis associated to antithyroid antibodies (SREAT). The median age was 62 years-old [14–88]. Females (62.8%) outnumbered males (37.2%). Limbic encephalitis was the most common clinical syndrome (60.5%), followed by SREAT (16.2%), autoimmune cerebellitis (9.3%), stiff-person syndrome (7%), antiNMDAR-encephalitis (5%) and antiIgLON5 encephalopathy (2%). CSF showed pleocytosis and/or hyperproteinorrhachia in 54.2%. MRI was unremarkable in 60%. Brain SPECT/PET showed hyperperfusion/hypermetabolism of limbic areas in 60% of patients to whom it was performed. Antibody-positivity was significantly associated with satisfaction of diagnostic criteria at high levels of certainty (p

Despite mitochondria being key for the control of cell homeostasis and fate, their role in DNA damage response is usually just regarded as an apoptotic trigger. However, growing evidence points to mitochondrial factors modulating nuclear functions. Remarkably, after DNA damage, cytochrome c (Cc) interacts in the cell nucleus with a variety of well‐known histone chaperones, whose activity is competitively inhibited by the haem protein. As nuclear Cc inhibits the nucleosome assembly/disassembly activity of histone chaperones, it might indeed affect chromatin dynamics and histone deposition on DNA. Several histone chaperones actually interact with Cc Lys residues through their acidic regions, which are also involved in heterotypic interactions leading to liquid–liquid phase transitions responsible for the assembly of nuclear condensates, including heterochromatin. This relies on dynamic histone–DNA interactions that can be modulated by acetylation of specific histone Lys residues. Thus, Cc may have a major regulatory role in DNA repair by fine‐tuning nucleosome assembly activity and likely nuclear condensate formation.

Trichomonas gallinae is a flagellated protozoan that parasitizes the upper digestive tract of various bird species and causes avian trichomonosis. The emergence of resistant strains to the standard treatment, based on nitroimidazoles, increases the need to find alternative therapies. In this study, 36 essential oils (EOs) from Lamiaceae and Asteraceae plant families were tested against T. gallinae trophozoites using the 3-(4,5-dimethylthiazol-2-yl-)-2,5-dipheniltetrazolium bromide (MTT) reduction assay. Among them, EOs from distinct species of Lamiaceae, including the genera Lavandula, Salvia, Thymus, Origanum, and Satureja were the ones reporting better anti-trichomonal activity, and were selected for further analysis, including chemical composition and in vitro assays. The chemical composition of the selected EOs was determined by gas chromatography followed by mass spectrometry and 19 pure compounds were tested against the protozoa, according to their higher abundance in the active EOs. Pure compounds which displayed the highest activity against T. gallinae trophozoites, ordered by highest to lowest activity, were α and β-thujones, camphene, β-pinene, linalyl acetate, thymol, 4-terpineol, γ-terpinene, α-pinene, p-cymene, D-fenchone and β-caryophyllene. A dose dependent effect was observed in most of the EOs and pure compounds tested. The toxicity test conducted in eukaryotic cell cultures with the anti-trichomonal active pure compounds showed that β-caryophyllene, camphene, α-pinene, and β-pinene were slightly toxic for Vero cells, and the selectivity index was calculated. Based on the anti-trichomonal activity and the absence of cytotoxicity results, natural products from Lamiaceae plants could be useful as alternative therapy against avian trichomonosis, mainly those containing linalyl acetate, thymol, 4-terpinenol, γ-terpinene, p-cymene and D-fenchone.

Stress granules are non-membrane bound RNA-protein granules essential for survival during acute cellular stress. TIA-1 is a key protein in the formation of stress granules that undergoes liquid-liquid phase separation by association with specific RNAs and protein-protein interactions. However, the fundamental properties of the TIA-1 protein that enable phase-separation also render TIA-1 susceptible to the formation of irreversible fibrillar aggregates. Despite this, within physiological stress granules, TIA-1 is not present as fibrils, pointing to additional factors within the cell that prevent TIA-1 aggregation. Here we show that heterotypic interactions with stress granule co-factors Zn2+ and RGG-rich regions from FUS each act together with nucleic acid to induce the liquid-liquid phase separation of TIA-1. In contrast, these co-factors do not enhance nucleic acid induced fibril formation of TIA-1, but rather robustly inhibit the process. NMR titration experiments revealed specific interactions between Zn2+ and H94 and H96 in RRM2 of TIA-1. Strikingly, this interaction promotes multimerization of TIA-1 independently of the prion-like domain. Thus, through different molecular mechanisms, these stress granule co-factors promote TIA-1 liquid-liquid phase separation and suppress fibrillar aggregates, potentially contributing to the dynamic nature of stress granules and the cellular protection that they provide.

Diet is one of the main sources of exposure to toxic chemicals with carcinogenic potential, some of which are generated during food processing, depending on the type of food (primarily meat, fish, bread and potatoes), cooking methods and temperature. Although demonstrated in animal models at high doses, an unequivocal link between dietary exposure to these compounds with disease has not been proven in humans. A major difficulty in assessing the actual intake of these toxic compounds is the lack of standardised and harmonised protocols for collecting and analysing dietary information. The intestinal microbiota (IM) has a great influence on health and is altered in some diseases such as colorectal cancer (CRC). Diet influences the composition and activity of the IM, and the net exposure to genotoxicity of potential dietary carcinogens in the gut depends on the interaction among these compounds, IM and diet. This review analyses critically the difficulties and challenges in the study of interactions among these three actors on the onset of CRC. Machine Learning (ML) of data obtained in subclinical and precancerous stages would help to establish risk thresholds for the intake of toxic compounds generated during food processing as related to diet and IM profiles, whereas Semantic Web could improve data accessibility and usability from different studies, as well as helping to elucidate novel interactions among those chemicals, IM and diet.

In response to liver injury, hepatic stellate cells activate and acquire proliferative and contractile features. The regression of liver fibrosis appears to involve the clearance of activated hepatic stellate cells, either by apoptosis or by reversion toward a quiescent-like state, a process called deactivation. Thus, deactivation of active hepatic stellate cells has emerged as a novel and promising therapeutic approach for liver fibrosis. However, our knowledge of the master regulators involved in the deactivation and/or activation of fibrotic hepatic stellate cells is still limited. The transcription factor GATA4 has been previously shown to play an important role in embryonic hepatic stellate cell quiescence. In this work, we show that lack of GATA4 in adult mice caused hepatic stellate cell activation and, consequently, liver fibrosis. During regression of liver fibrosis, Gata4 was reexpressed in deactivated hepatic stellate cells. Overexpression of Gata4 in hepatic stellate cells promoted liver fibrosis regression in CCl4-treated mice. GATA4 induced changes in the expression of fibrogenic and antifibrogenic genes, promoting hepatic stellate cell deactivation. Finally, we show that GATA4 directly repressed EPAS1 transcription in hepatic stellate cells and that stabilization of the HIF2α protein in hepatic stellate cells leads to liver fibrosis.

La sexualidad de las personas con discapacidad intelectual (DI) ha sido un tema muy controvertido. Su sexualidad ha estado sustentada por una serie de mitos y falsas creencias que, a pesar de carecer de apoyo empírico, han restringido su derecho a conseguir una expresión libre de esta faceta. En unos casos su sexualidad ha sido equiparada a la de los niños, creyendo que eran personas asexuadas; y en otros se les ha presupuesto una ausencia de control sobre sus impulsos, optando por no despertar sus instintos sexuales. El equipo SALUSEX inició el estudio de la sexualidad en este colectivo en el año 2015 con un proyecto financiado por el Ministerio de Economía y Competitividad relacionado con la calidad de vida y las secuelas del abuso sexual. Dadas las carencias y necesidades observadas, a este primer proyecto le siguió otro, actualmente en desarrollo, cuyo objetivo es la elaboración y el análisis de la eficacia de un programa de prevención del abuso y mejora de la salud sexual mediante el cual se están desarrollando y validando instrumentos psicométricos para recoger información sobre sus conocimientos, creencias y experiencias tanto de forma autoinformada como heteroinformada. Así, el presente trabajo tiene como propósito presentar algunos instrumentos para la evaluación de la sexualidad en el ámbito de la diversidad funcional intelectual desarrollados por el equipo Salusex.

Post-translational modifications of proteins expand their functional diversity, regulating the response of cells to a variety of stimuli. Among these modifications, phosphorylation is the most ubiquitous and plays a prominent role in cell signaling. The addition of a phosphate often affects the function of a protein by altering its structure and dynamics. However, these alterations are often difficult to study and the functional and structural implications remain unresolved. New approaches are emerging to overcome common obstacles related to the production and manipulation of these samples. Here, we summarize the available methods for phosphoprotein purification and phosphomimetic engineering, highlighting the advantages and disadvantages of each. We propose a general workflow for protein phosphorylation analysis combining computational and biochemical approaches, building on recent advances that enable user-friendly and easy-to-access Molecular Dynamics simulations. We hope this innovative workflow will inform the best experimental approach to explore such post-translational modifications. We have applied this workflow to two different human protein models: the hemeprotein cytochrome c and the RNA binding protein HuR. Our results illustrate the usefulness of Molecular Dynamics as a decision-making tool to design the most appropriate phosphomimetic variant.

La superposición entre los trastornos del espectro autista (TEA) y los trastornos de la conducta alimentaria (TCA) lleva tiempo estudiándose, encontrándose sobre todo similitudes en ciertas características cognitivas. El objetivo de este trabajo es analizar la bibliografía disponible acerca de la relación entre los síntomas que corresponden al espectro autista con las diferentes patologías que se engloban dentro de los TCA. La información fue recogida a partir de diferentes bases de datos (Pubmed, Cochrane, Tripdatabase, UpToDate) entre 2013 y 2018. Se emplean los descriptores “eating disorders”, “autism”, “treatment”, “psychotherapy”, “anorexia nervosa”, “bulimia nervosa”, “food avoidant/restriction intake disorder” “binge eating disorder” “obesity” y “adolescence”; así como sus equivalentes en español. Los estudios publicados, referidos a lo largo del texto, sobre todo se refieren a la anorexia nerviosa (AN), existiendo menos investigaciones realizadas con otras patologías alimentarias como obesidad, bulimia, y trastorno por atracón. Sin embargo, y a pesar que sobre todo se señale la relación con la AN, existen características a nivel cognitivo que son compartidas entre los TCA y los TEA que han de ser tenidas en cuenta por sus implicaciones tanto en el tratamiento como en el pronóstico.

Background: Even though liver kinase B1 (LKB1) is usually described as a tumor suppressor in a wide variety of tissues, it has been shown that LKB1 aberrant expression is associated with bad prognosis in Hepatocellular Carcinoma (HCC). Methods: Herein we have overexpressed LKB1 in human hepatoma cells and by using histidine pull-down assay we have investigated the role of the hypoxia-related post-translational modification of Small Ubiquitin-related Modifier (SUMO)ylation in the regulation of LKB1 oncogenic role. Molecular modelling between LKB1 and its interactors, involved in regulation of LKB1 nucleocytoplasmic shuttling and LKB1 activity, was performed. Finally, high affinity SUMO binding entities-based technology were used to validate our findings in a pre-clinical mouse model and in clinical HCC. Findings: We found that in human hepatoma cells under hypoxic stress, LKB1 overexpression increases cell viability and aggressiveness in association with changes in LKB1 cellular localization. Moreover, by using site-directed mutagenesis, we have shown that LKB1 is SUMOylated by SUMO-2 at Lys178 hampering LKB1 nucleocytoplasmic shuttling and fueling hepatoma cell growth. Molecular modelling of SUMO modified LKB1 further confirmed steric impedance between SUMOylated LKB1 and the STe20-Related ADaptor cofactor (STRADα), involved in LKB1 export from the nucleus. Finally, we provide evidence that endogenous LKB1 is modified by SUMO in pre-clinical mouse models of HCC and clinical HCC, where LKB1 SUMOylation is higher in fast growing tumors. Interpretation: Overall, SUMO-2 modification of LKB1 at Lys178 mediates LKB1 cellular localization and its oncogenic role in liver cancer. Fund: This work was supported by grants from NIH (US Department of Health and Human services)-R01AR001576-11A1 (J.M.M and M.L.M-C.), Gobierno Vasco-Departamento de Salud 2013111114 (to M.L.M.-C), ELKARTEK 2016, Departamento de Industria del Gobierno Vasco (to M.L.M.-C), MINECO: SAF2017–87301-R and SAF2014–52097-R integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovación 2013–2016 cofinanciado con Fondos FEDER (to M.L.M.-C and J.M.M., respectively), BFU2015–71017/BMC MINECO/FEDER, EU (to A.D.Q. and I.D.M.), BIOEF (Basque Foundation for Innovation and Health Research): EITB Maratoia BIO15/CA/014; Instituto de Salud Carlos III:PIE14/00031, integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovacion 2013–2016 cofinanciado con Fondos FEDER (to M.L.M.-C and J.M.M), Asociación Española contra el Cáncer (T.C.D, P·F-T and M.L.M-C), Daniel Alagille award from EASL (to T.C.D), Fundación Científica de la Asociación Española Contra el Cancer (AECC Scientific Foundation) Rare Tumor Calls 2017 (to M.L.M and M.A), La Caixa Foundation Program (to M.L.M), Programma di Ricerca Regione-Università 2007–2009 and 2011–2012, Regione Emilia-Romagna (to E.V.), Ramón Areces Foundation and the Andalusian Government (BIO-198) (A.D.Q. and I.D.M.), ayudas para apoyar grupos de investigación del sistema Universitario Vasco IT971–16 (P.A.), MINECO:SAF2015–64352-R (P.A.), Institut National du Cancer, FRANCE, INCa grant PLBIO16–251 (M.S.R.), MINECO - BFU2016–76872-R to (E.B.). Work produced with the support of a 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (M.V-R). Finally, Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III. We thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644). Funding sources had no involvement in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Keywords: LKB1, SUMO, HCC, SIRT1, STRADα

Repair of injured DNA relies on nucleosome dismantling by histone chaperones and de-phosphorylation events carried out by Protein Phosphatase 2A (PP2A). Typical histone chaperones are the Acidic leucine-rich Nuclear Phosphoprotein 32 family (ANP32) members, e.g. ANP32A, which is also a well-known PP2A inhibitor (a.k.a. I1PP2A). Here we report the novel interaction between the endogenous family member B—so-called ANP32B—and endogenous cytochrome c in cells undergoing camptothecin-induced DNA damage. Soon after DNA lesions but prior to caspase cascade activation, the hemeprotein translocates to the nucleus to target the Low Complexity Acidic Region (LCAR) of ANP32B; in a similar way, our group recently reported that the hemeprotein targets the acidic domain of SET/Template Activating Factor-Iβ (SET/TAF-Iβ), which is another histone chaperone and PP2A inhibitor (a.k.a. I2PP2A). The nucleosome assembly activity of ANP32B is indeed unaffected by cytochrome c binding. Like ANP32A, ANP32B inhibits PP2A activity and is thus herein referred to as I3PP2A. Our data demonstrates that ANP32B-dependent inhibition of PP2A is regulated by respiratory cytochrome c, which induces long-distance allosteric changes in the structured N-terminal domain of ANP32B upon binding to the C-terminal LCAR. In agreement with the reported role of PP2A in the DNA damage response, we propose a model wherein cytochrome c is translocated from the mitochondria into the nucleus upon DNA damage to modulate PP2A activity via its interaction with ANP32B.

Cell signaling mechanisms modulate gene expression in response to internal and external stimuli. Cellular adaptation requires a precise and coordinated regulation of the transcription and translation processes. The post-transcriptional control of mRNA metabolism is mediated by the so-called RNA-binding proteins (RBPs), which assemble with specific transcripts forming messenger ribonucleoprotein particles of highly dynamic composition. RBPs constitute a class of trans-acting regulatory proteins with affinity for certain consensus elements present in mRNA molecules. However, these regulators are subjected to post-translational modifications (PTMs) that constantly adjust their activity to maintain cell homeostasis. PTMs can dramatically change the subcellular localization, the binding affinity for RNA and protein partners, and the turnover rate of RBPs. Moreover, the ability of many RBPs to undergo phase transition and/or their recruitment to previously formed membrane-less organelles, such as stress granules, is also regulated by specific PTMs. Interestingly, the dysregulation of PTMs in RBPs has been associated with the pathophysiology of many different diseases. Abnormal PTM patterns can lead to the distortion of the physiological role of RBPs due to mislocalization, loss or gain of function, and/or accelerated or disrupted degradation. This Mini Review offers a broad overview of the post-translational regulation of selected RBPs and the involvement of their dysregulation in neurodegenerative disorders, cancer and other pathologies.

While most organelles are surrounded by membranes, cells also contain membraneless organelles, which remain separated in the cell by avoiding the mixture of their components with the surroundings. Actually, liquid–liquid phase separation provides a simple but smart mechanism for the cell to control the spatial localization and processing of molecules, without relying on membrane boundaries. This Special ‘In the Limelight’ section, entitled ‘Membraneless organelles’, consists of three review articles, each focused on a particular aspect. The first article deals with assembly of coacervates as mediated by polyproline II helices, as well as with condensate stability. The second article addresses the formation of protein–nucleic acid coacervates by prion‐like proteins and their link to human diseases. Finally, the last article focuses on mitochondrial cytochrome c translocation into the nucleus after DNA damage, with the subsequent inhibition of nucleosome assembly/disassembly activity of histone chaperones and its impact on chromatin dynamics and nuclear condensates.

The nucleotides involved in RNA-RNA interaction can be tagged by chemical- or UV-induced crosslinking, and further identified by classical or modern high throughput techniques. The contacts of mRNA with 18S rRNA that occur along the mRNA channel of 40S subunit have been mapped by site-specific UV crosslinking followed by reverse transcriptase termination sites (RTTS) using radioactive or fluorescent oligonucleotides. However, the sensitivity of this technique is restricted to the detection of those fragments that resulted from the most frequent crosslinkings. Here, we combined RTTS with RNAseq to map the mRNA-18S rRNA contacts with a much deeper resolution. Although aimed to detect the interaction of mRNA with the ES6S region of 18S rRNA, this technique can also be applied to map the interaction of mRNA with other non-coding RNA molecules (e.g., snRNAs, microRNAs and lncRNAs) during transcription, splicing or RNA-mediated postranscriptional regulation.

The proper arrangement of protein components within the respiratory electron transport chain is nowadays a matter of intense debate, since altering it leads to cell aging and other related pathologies. Here, we discuss three current views—the so-called solid, fluid and plasticity models—which describe the organization of the main membrane-embedded mitochondrial protein complexes and the key elements that regulate and/or facilitate supercomplex assembly. The soluble electron carrier cytochrome c has recently emerged as an essential factor in the assembly and function of respiratory supercomplexes. In fact, a ‘restricted diffusion pathway’ mechanism for electron transfer between complexes III and IV has been proposed based on the secondary, distal binding sites for cytochrome c at its two membrane partners recently discovered. This channeling pathway facilitates the surfing of cytochrome c on both respiratory complexes, thereby tuning the efficiency of oxidative phosphorylation and diminishing the production of reactive oxygen species. The well-documented post-translational modifications of cytochrome c could further contribute to the rapid adjustment of electron flow in response to changing cellular conditions. Keywords: Cytochrome c, Mitochondria, Phosphorylation, Reactive oxygen species, Respiratory supercomplexes

Electron transport chains rely on interactions between redox proteins, but the distance-dependence of the electron transfer rate through the solution is unknown. Here, the authors show that the current between two redox protein partners occurs at long distances and is electrochemically gated.

Multiple definitions have been put forward in the literature to measure the differences between two interval-valued fuzzy sets. However, in most cases, the outcome is just a real value, although an interval could be more appropriate in this environment. This is the starting point of this contribution. Thus, we revisit the axioms that a measure of the difference between two interval-valued fuzzy sets should satisfy, paying special attention to the condition of monotonicity in the sense that the closer the intervals are, the smaller the measure of difference between them is. Its formalisation leads to very different concepts: distances, divergences and dissimilarities. We have proven that distances and divergences lead to contradictory properties for this kind of sets. Therefore, we conclude that dissimilarities are the only appropriate measures to measure the difference between two interval-valued fuzzy sets when the outcome is an interval.

The optimization of conditions to promote the stemness of pluripotent cells in vitro is instrumental for their use in advanced therapies. We show here that exposure of human iPSCs and human ESCs to low concentrations of the chemical NO donor DETA/NO leads to stabilization of hypoxia-inducible factors (HIF-1α and HIF-2α) under normoxia, with this effect being dependent on diminished Pro 402 hydroxylation and decreased degradation by the proteasome. Moreover, the master genes of pluripotency, NANOG and OCT-4, were upregulated. NO also induces a shift in the metabolic profile of PSCs, with an increased expression of hypoxia response genes in glycolysis. Furthermore, a reduction in the mitochondrial membrane potential with lower oxygen consumption and increased expression of mitochondrial fusion regulators, such as DRP1, was observed. The results reported here indicate that NO mimics hypoxia response in human PSCs and enhances their stemness properties when cultured under normoxic conditions.

ZnO nanoparticles (ZnONPs) have been shown to have therapeutic potential in some diseases such as diabetes and cancer. However, concentration-dependent adverse effects have also been reported. Studies which evaluate the effects of ZnONPs on the cardiovascular system are scarce. This study aimed to evaluate the cardiovascular effects of a low dose of ZnONPs administered chronically in healthy rats. Changes in dyslipidemia biomarkers, blood pressure, aortic wall structure, vascular contractility, and expression of cannabinoid receptors in the aorta wall were evaluated. Healthy rats were divided into two groups: control or treated (one, two, and three months). The treated rats received an oral dose of 10 mg/kg/day. The results showed that treatment with ZnONPs induced dyslipidemia from the first month, increasing atherosclerosis risk, which was confirmed by presence of atherosclerotic alterations revealed by aorta histological analysis. In in vitro assays, ZnONPs modified the aorta contractile activity in response to the activation of cannabinoid receptors (CB1 and CB2). The expression of CB1 and CB2 was modified as well. Moreover, ZnONPs elicited an increase in blood pressure. In conclusion, long-time oral administration of ZnONPs induce dyslipidemia and atherosclerosis eliciting alterations in aorta contractility, CB1 and CB2 receptors expression, and an increase in blood pressure in healthy rats.

Sexual abuse is a problem that affects, especially, people with intellectual disabilities. In order to cope with this, the role of professionals is essential for both the identification and the prevention and treatment of this problem. However, there are few studies focus on what extent the professionals’ evaluation agree the real experience of the people with intellectual disability. For this reason, the present study analyses risk perception and experience of sexual abuse suffered by people with intellectual disability, compared to the identification and evaluation of professionals who attend them. For this purpose, 154 adults with intellectual disabilities and 16 professionals completed the DAS, the ECS and the ECS-R respectively. The results show how sexual abuse is a reality for people with intellectual disabilities although they do not always manifest receiving, sometimes, rejection by their close people. Moreover, gender differences are shown, in which women suffer sexual abuse and its consequences more frequently. Professionals only realize about some part of this situation and they attribute greater vulnerability to women and those who have already suffered a prior episode of sexual abuse. In this sense, it would be essential to have programs for the detection and treatment of sexual abuse, considering that professionals are a positive reference for people with intellectual disabilities

Negative attitudes towards sexuality of people with disabilities are the main impediment to their psychosexual development. This paper analyzes the attitudes towards sexuality of people with physical and intellectual disabilities in parents, professionals who work with them and the general population. For this purpose, we use the Attitudes toward Sexuality in Persons with Intellectual Disability Scale (ASEXDI) and the Attitudes toward Sexuality in Persons with Physical Disability Scale (ASEXDF) in a sample of 300 people: 100 family members, 100 professionals and 100 people from the general population. The results indicate that parents have more conservative attitudes than the professionals who work with this group. General population have more favorable sexual attitudes towards people with physical disabilities than people with intellectual disabilities. We must work to improve attitudes towards sexuality of people with disabilities to achieve a free and adequate expression of their sexuality.

Loading of mRNA onto the ribosomal 43S pre-initiation complex (PIC) and its subsequent scanning require the removal of the secondary structure of the by RNA helicases such as eIF4A. However, the topology and mechanics of the scanning complex bound to mRNA (48S-PIC) and the influence of its solvent-side composition on the scanning process are poorly known. Here, we found that the ES6S region of the 48S-PIC constitutes an extended binding channel for eIF4A-mediated unwinding of mRNA and scanning. Blocking ES6S inhibited the cap-dependent translation of mRNAs that have structured 5′ UTRs (including G-quadruplexes), many of which are involved in signal transduction and growth, but it did not affect IRES-driven translation. Genome-wide analysis of mRNA translation revealed a great diversity in ES6S-mediated scanning dependency. Our data suggest that mRNA threading into the ES6S region makes scanning by 48S PIC slower but more processive. Hence, we propose a topological and functional model of the scanning 48S-PIC.

Preference aggregation and in particular ranking aggregation are mainly studied by the field of social choice theory but extensively applied in a variety of contexts. Among the most prominent methods for ranking aggregation, the Kemeny method has been proved to be the only one that satisfies some desirable properties such as neutrality, consistency and the Condorcet condition at the same time. Unfortunately, the problem of finding a Kemeny ranking is NP-hard, which prevents practitioners from using it in real-life problems. The state of the art of exact algorithms for the computation of the Kemeny ranking experienced a major boost last year with the presentation of an algorithm that provides searching time guarantee up to 13 alternatives. In this work, we propose an enhanced version of this algorithm based on pruning the search space when some Condorcet properties hold. This enhanced version greatly improves the performance in terms of runtime consumption.

The importance that mature adults give to the fact of having an active sexual behavior is increasing. However, this interest clashes with physical limitations that the old age imposes. The aim of this study was to study sexual behavior among mature adults through the use of one of the most employed questionnaires for its assessment: the International Index of Erectile Function. For this purpose, 38 males between 53 and 81 years old completed the study surveys. We found that whereas some aspects of sexual behavior (e.g., the erectile function or the sexual desire) were adversely affected in mature adults, the impact on other domains such as the global sexual satisfaction is limited. This study increases our knowledge about sexuality in the adulthood and improves our preventive and therapeutic interventions on this collective

Las principales causas de mortalidad y morbilidad entre la población se relaciona con el estilo de vida. Con el objetivo de examinar los efectos de la personalidad en los cuidados de salud en diferentes áreas, se evaluaron a 200 jóvenes de la Comunidad Valenciana (Medad = 20,92; DT = 2,25). Se utilizaron la Escala de Cuidados de Salud y el Inventario de Personalidad NEO PI-R. Los jóvenes cuidan su salud una media de 62.83 puntos (DT=12.19) sobre un máximo de 110 puntos. Los hábitos de salud más cuidados son la conducción, la higiene y la sexualidad. Por el contrario, los menos cuidados son el ejercicio físico, el consumo de alcohol y las revisiones médicas. El análisis de las correlaciones muestra que los jóvenes con mayores puntuaciones en Responsabilidad cuidan en mayor medida la mayoría de las áreas de salud evaluadas. Por el contrario, las personas con mayor Neuroticismo, cuidan menos la alimentación, el ejercicio físico, el consumo de tabaco y otras drogas. La dimensión Extraversión correlaciona positivamente con el cuidado en alimentación y hábitos sexuales. La Apertura a la Experiencia se relaciona de manera positiva con el cuidado de la alimentación y de la exposición al sol. Y, por último, la Amabilidad correlaciona positivamente con el cuidado del consumo de alcohol, tabaco, otras drogas y conducción. El análisis de regresión indica que Amabilidad y Responsabilidad explican el 18.2% de la varianza de los cuidados sobre la salud. Las características individuales de las personas, consideradas como agentes activos, constituyen una de las claves más importantes para entender los procesos involucrados en la adquisición, mantenimiento o deterioro de su propia salud.

The quality of life in the Intellectual Disabled people assessed by themselves and by their professionals: implicated variables. Improving the quality of life of people with intellectual disabilities is a prioritary goal since the implementation of the Law on Promotion of Personal Autonomy and Care for dependent people. Professionals and users do not always agree with the assessment about the different construct dimensions. Discrepancies may be due to variables not specifically analyzed by the research like the way they live, or the degree of disability that they have. The aim of this study was to analyze the possible discrepancies between the assessments of both informants attending these features. To this objective the INICO-FEAPS scale was applied to 360 adults with intellectual disability and 103 professionals working with them. The results show agreement in 5 of the scale dimensions, like Rights, Physical and Material Well-being; on the other hand we have found large discrepancies in Self-determination and Emotional Well-being. Results are interpretated in light of the kind of needs of the dimensions of quality of life.

El ajuste diádico no solamente es un factor esencial en la perdurabilidad y calidad de toda relación de pareja, sino que además, puede afectar a la vida personal y a la salud de sus miembros. El presente estudio explora el ajuste percibido por las personas mayores en España en su relación de pareja presente o pasada, analizando las posibles diferencias entre hombres y mujeres. Se administró la Escala de Ajuste Diádico a 80 personas entre los 51 y los 81 años. El 55% eran mujeres. El 66,3% estaban casados, el 21,3% separados o divorciados y un 12,5% había enviudado. Se tomó el valor 107 propuesto en la literatura como punto de corte para establecer un ajuste diádico positivo. La puntuación global media en el total de población fue 101,47 (DT = 21,75). Los hombres presentan una mayor puntuación que las mujeres en la escala global y en cada una de sus dimensiones, pero únicamente se halló diferencias significativas en la escala Consenso (hombres: 48,87 vs mujeres: 41,17; p=0,042). Los resultados muestran la influencia de los roles de género tradicionales en la valoración percibida de la relación de pareja y la necesidad de establecer estrategias clínicas y sociales para favorecer el disfrute y la armonía en las parejas de personas mayores.

Different studies in experimental diabetes models suggest that zinc oxide nanoparticles (ZnONPs) are useful as antidiabetic agents. However, this evidence was performed and measured in long-term treatments and with repeated doses of ZnONPs. This work aimed to evaluate the ZnONPs acute effects on glycemia during the next six h after an oral or intraperitoneal administration of the treatment in healthy and diabetic rats. In this study, the streptozotocin-nicotinamide intraperitoneal administration in male Wistar rats were used as a diabetes model. 10 mg/kg ZnONPs did not modify the baseline glucose in any group. Nevertheless, the ZnONPs short-term administration (100 mg/kg) induced a hyperglycemic response in a dose and route-dependent administration in healthy (130 ± 2 and 165 ± 10 mg/dL with oral and intraperitoneal, respectively) and diabetic rats (155 ± 2 and 240 ± 20 mg/dL with oral, and intraperitoneal, respectively). The diabetic rats were 1.5 fold more sensitive to ZnONPs effect by the intraperitoneal route. In conclusion, this study provides new information about the acute response of ZnONPs on fasting glycemia in diabetic and healthy rat models; these data are essential for possible future clinical approaches.