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The evolution of facultative symbiosis in stony corals
(Nature Research, 2025) Levy, Shani; Grau Bové, Xavier; Kim, Iana V.; Najle, Sebastián R.; Ksiezopolska, Ewa; Elek, Anamaria; Montes-Espuña, Laia; Montgomery, Sean A.; Mass, Tali; Sebé-Pedrós, Arnau
Most stony corals are obligate symbionts that are dependent on nutrients provided by the photosynthetic activity of dinoflagellates residing within specialized cells1. Disruption of this symbiotic consortium leads to coral bleaching and, ultimately, mortality2. However, a few coral species exhibit facultative symbiosis, allowing them to survive extended periods of bleaching3,4. Despite this resilience, the underlying biological mechanisms remain poorly understood. Here we investigate the genomic and cellular basis of facultative symbiosis in Oculina patagonica, a thermotolerant Mediterranean coral5,6. We sequenced and annotated a chromosome-scale genome of O. patagonica and built cell atlases for this species and two obligate symbiotic corals. Comparative genomic analysis revealed karyotypic and syntenic conservation across all scleractinians, with species-specific gene expansions primarily driven by tandem duplications. Single-cell transcriptomic profiling of symbiotic and naturally aposymbiotic wild specimens identified an increase in phagocytic immune cells and a metabolic shift in gastrodermal gene expression from growth-related functions to quiescent, epithelial-like states. Cross-species comparison of host cells uncovered Oculina-specific metabolic and signalling adaptations indicative of an opportunistic, dual-feeding strategy that decouples survival from symbiotic state.
Neurodevelopmental disorders: 2024 update
(University of Münster, 2024) Martínez de Lagrán Cabredo, María; Bascón-Cardozo, Karen; Dierssen, Mara
Neurodevelopmental disorders encompass a range of conditions such as intellectual disability, autism spectrum disorder, rare genetic disorders and developmental and epileptic encephalopathies, all manifesting during childhood. Over 1,500 genes involved in various signaling pathways, including numerous transcriptional regulators, spliceosome elements, chromatin-modifying complexes and de novo variants have been recognized for their substantial role in these disorders. Along with new machine learning tools applied to neuroimaging, these discoveries facilitate genetic diagnoses, providing critical insights into neuropathological mechanisms and aiding in prognosis, and precision medicine. Also, new findings underscore the importance of understanding genetic contributions beyond protein-coding genes and emphasize the role of RNA and non-coding DNA molecules but also new players, such as transposable elements, whose dysregulation generates gene function disruption, epigenetic alteration, and genomic instability. Finally, recent developments in analyzing neuroimaging now offer the possibility of characterizing neuronal cytoarchitecture in vivo, presenting a viable alternative to traditional post-mortem studies. With a recently launched digital atlas of human fetal brain development, these new approaches will allow answering complex biological questions about fetal origins of cognitive function in childhood. In this review, we present ten fascinating topics where major progress has been made in the last year.
Methods for identifying epilepsy surgery targets using invasive EEG: a systematic review
(MDPI, 2024) Ivankovic, Karla; Principe, Alessandro; Zucca, Riccardo; Dierssen, Mara; Rocamora Zúñiga, Rodrigo Alberto
Background: The pre-surgical evaluation for drug-resistant epilepsy achieves seizure freedom in only 50-60% of patients. Efforts to identify quantitative intracranial EEG (qEEG) biomarkers of epileptogenicity are needed. This review summarizes and evaluates the design of qEEG studies, discusses barriers to biomarker adoption, and proposes refinements of qEEG study protocols. Methods: We included exploratory and prediction prognostic studies from MEDLINE and Scopus published between 2017 and 2023 that investigated qEEG markers for identifying the epileptogenic network as the surgical target. Cohort parameters, ground truth references, and analytical approaches were extracted. Results: Out of 1789 search results, 128 studies were included. The study designs were highly heterogeneous. Half of the studies included a non-consecutive cohort, with sample sizes ranging from 2 to 166 patients (median of 16). The most common minimum follow-up was one year, and the seizure onset zone was the most common ground truth. Prediction studies were heterogeneous in their analytical approaches, and only 25 studies validated the marker through post-surgical outcome prediction. Outcome prediction performance decreased in larger cohorts. Conversely, longer follow-up periods correlated with higher prediction accuracy, and connectivity-based approaches yielded better predictions. The data and code were available in only 9% of studies. Conclusions: To enhance the validation qEEG markers, we propose standardizing study designs to resemble clinical trials. This includes using a consecutive cohort with long-term follow-up, validating against surgical resection as ground truth, and evaluating markers through post-surgical outcome prediction. These considerations would improve the reliability and clinical adoption of qEEG markers.
A multimodal lifestyle intervention complemented with epigallocatechin gallate to prevent cognitive decline in APOE- ɛ4 carriers with Subjective Cognitive Decline: a randomized, double-blinded clinical trial (PENSA study)
(Elsevier, 2025) Forcano, Laura; Soldevila-Domenech, Natalia; Boronat Rigol, Anna, 1990-; Sánchez Benavides, Gonzalo; Puig-Pijoan, Albert; Lorenzo, Thais; Aldea-Perona, Ana; Suárez-Calvet, Marc; Cuenca Royo, Aida Ma, 1981-; Gispert López, Juan Domingo; Gomis González, Maria, 1988-; Minguillón, Carolina; Diaz-Pellicer, Patricia; Piera, Iris; Langohr, Klaus; Dierssen, Mara; Pizarro Lozano, Mª Nieves; Mur-Gimeno E.; Grau-Rivera, Oriol; Molinuevo, José Luis; Torre Fornell, Rafael de la; PENSA working group
Background: The potential of dietary compounds to enhance the effects of multimodal lifestyle interventions (MLIs) on cognition in individuals at high risk of cognitive impairment remains unclear. Objectives: To assess whether the addition of a green tea extract enriched with epigallocatechin-3-gallate (EGCG) enhances the effects of an MLI. Design: Double-blind, randomized, two-arm, and placebo-controlled trial. Exploratory comparisons were made with a non-randomized group (NRG) receiving healthy lifestyle recommendations. Setting: Population-based study conducted in Barcelona, Spain PARTICIPANTS: APOE-ɛ4 carriers aged 60-80 with subjective cognitive decline INTERVENTION: A 12-month intensive MLI including dietary counseling, guided physical activity, and cognitive stimulation, combined with EGCG (5-6 mg/kg) or placebo, followed by a 3-month washout. Measurements: Primary endpoint was change in the modified Preclinical Alzheimer Cognitive Composite (PACC-exe) score. Results: 129 participants (65.1% 84 women, aged 66.7±5.5 years) were enrolled (52 MLI+EGCG, 52 MLI+placebo and 25 NRG), with126 (97.7%) included in the modified intention-to-treat analysis. After 12 months, no statistically significant difference was observed between MLI+EGCG and MLI+placebo in the PACC-exe (adjusted mean difference [AMD]: 0.12; 95%CI: -0.01, 0.24; p=0.061). However, participants in the MLI+EGCG group were 2.6 times more likely to show a reliable cognitive improvement. In exploratory analyses following a 3-month washout, the MLI+EGCG group showed significant cognitive benefits compared to the MLI+placebo (AMD: 0.19; 95%CI: 0.06, 0.32; p=0.005). Exploratory comparisons with the NRG also suggested greater gains in cognition and dementia risk reduction in both MLI groups, particularly with EGCG. Conclusions: While the primary outcome was not met, this proof-of-concept trial suggests that combining MLIs with EGCG warrants further investigation in larger, confirmatory studies.
Emergence of activation or repression in transcriptional control under a fixed molecular context
(National Academy of Sciences, 2025) Martinez-Corral, Rosa; Friedrich, Dhana; Frömel, Robert; Velten, Lars; Gunawardena, Jeremy; DePace, Angela H.
Transcription factors (TFs) can be both activators and repressors of gene transcription. This can manifest as "duality," where the transcriptional response increases (activation) with TF concentration in one context but decreases (repression) in another context, or as "nonmonotonicity," where, in the same context, the response increases in part of the concentration range and decreases outside that range. Here we use biophysical models of gene regulation to investigate how duality and nonmonotonicity relate to the interactions between a TF, Polymerase and the regulatory DNA. We distinguish two modes of TF action on Polymerase: "coherent," with interactions either positive or negative, and "incoherent," where interactions are a mix of both. For TFs that act incoherently from a single TF-DNA binding site, nonmonotonicity can arise, but only under nonequilibrium models. For single-site models, we show that nonmonotonicity can never happen under the common thermodynamic models of gene regulation, which consider equilibrium conditions and ignore the dissipative nature of the transcription process. Moreover, we show that merely changing the TF-DNA binding affinity, while keeping other features fixed, can tune the response between activation and repression, with responses either evaluated as a function of TF concentration or site number. Using the mammalian Sp1 as a case study and synthetically designed target sequences, we find experimental evidence for nonmonotonicity, and activation or repression tuned by affinity, which we interpret as evidence of incoherent action. Our work highlights the importance of moving from a TF-centric view to a systems view when reasoning about transcriptional control.
Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicing
(Nature Research, 2025) Baeza Centurión, Pablo, 1989-; Miñana Gómez, Belén; Faure, Andre J.; Thompson, Mike; Bonnal, Sophie; Quarantani, Gioia; Clarke, Joseph; Lehner, Ben, 1978-; Valcárcel, J. (Juan)
While altered pre-mRNA splicing is a frequent mechanism by which genetic variants cause disease, the regulatory architecture of human exons remains poorly understood. Antisense oligonucleotides (AONs) that target pre-mRNA splicing have been approved as therapeutics for various pathologies including patient-customised treatments for rare diseases, but AON discovery is currently slow and expensive, limiting the wider adoption of the approach. Here we show that deep indel mutagenesis (DIM) -which can be made experimentally at very low cost - provides an efficient strategy to chart the regulatory landscape of human exons and rapidly identify candidate splicing-modulating oligonucleotides. DIM reveals autonomous effects of insertions, while systematic deletion scans delineate the checkerboard architecture of sequential enhancers and silencers in a model alternative exon. The results also suggest a mechanism for repression of transmembrane domain-encoding exons and for the generation of microexons. Leveraging deep learning tools, we provide a resource, DANGO, that predicts the splicing regulatory landscape of all human exons and can help to identify effective splicing-modulating antisense oligonucleotides.
QSample: an automated system for rapid monitoring of quality indicators in proteomics samples
(American Chemical Society (ACS), 2025) Olivella, Roger; Chiva, Cristina; Serret, Marc; Hermoso Pulido, Antonio; Borràs, Eva; Espadas, Guadalupe; Morales Sanfrutos, Julia; Pastor, Olga; Solé, Amanda; Ponomarenko, Julia; Sabidó Aguadé, Eduard, 1981-
Mass spectrometry-based proteomics is an essential technique in contemporary biomedicine, offering quantitative, sensitive, and rapid analysis of proteomes. Recent advancements in mass spectrometry have enabled the acquisition of data from increasingly large-scale experiments, often conducted in core facilities and research infrastructures. While automated tools exist to assess instrument performance using predefined control samples, the analysis of experimental samples typically occurs postacquisition, which can delay decision-making and lead to potential data integrity issues. To address these challenges, we developed QSample, an open-source automated system for rapidly monitoring quality indicators in proteomics samples during data collection. QSample enhances the quality control framework by facilitating prompt actions and fast decision-making, ensuring that proteomics core facilities deliver data that adhere to best research practices.
Evolutionary diversification of ancestral genes across vertebrates and insects
(BioMed Central, 2025) Mantica, Federica; Irimia Martínez, Manuel
Background: Vertebrates and insects diverged approximately 700 million years ago, and yet they retain a large core of conserved genes from their last common ancestor. These ancient genes present strong evolutionary constraints, which limit their overall sequence and expression divergence. However, these constraints can greatly vary across ancestral gene families and, in at least some cases, sequence and expression changes can have functional consequences. Importantly, overall patterns of sequence and expression divergence and their potential functional outcomes have never been explored in a genome-wide manner across large animal evolutionary distances. Results: We focus on approximately 7000 highly conserved genes shared between vertebrates and insects, and we investigate global patterns of molecular diversification driven by changes in sequence and gene expression. We identify molecular features generally linked to higher or lower diversification rates, together with gene groups with similar diversification profiles in both clades. Moreover, we discover that specific sets of genes underwent differential diversification during vertebrate and insect evolution, potentially contributing to the emergence of unique phenotypes in each clade. Conclusions: We generate a comprehensive dataset of measures of sequence and expression divergence across vertebrates and insects, which reveals a continuous spectrum of evolutionary constraints among highly conserved genes. These constraints are normally consistent between these two clades and are associated with specific molecular features, but in some cases we also identify instances of lineage-specific diversification likely linked to functional evolution.
Harmonizing genotype array data to understand genetic risk for brain amyloid burden in the AMYPAD PNHS Consortium
(Wiley, 2025) Luckett, Emma S.; Abakkouy, Yasmina; Lorenzini, Luigi; Collij, Lyduine E.; Vállez García, David; Visser, Pieter Jelle; den Braber, Anouk; Ritchie, Craig; Boada, Mercè; Genius, Patricia; Vilor Tejedor, Natàlia, 1988-; Gispert López, Juan Domingo; Vandenberghe, Rik; Barkhof, Frederik; Cleynen, Isabelle; AMYPAD Consortium
Introduction: We sought to harmonize genotype data from the predementia AMYPAD (Amyloid Imaging to Prevent Alzheimer's Disease) Consortium, compute polygenic risk scores (PRS), and determine their association with global amyloid deposition. Methods: Genetic data from five AMYPAD parent cohorts were harmonized, and PRS were computed for Alzheimer's disease (AD) susceptibility, cerebrospinal fluid (CSF) amyloid beta (Aβ)42, and CSF phosphorylated tau181. Cross-sectional amyloid (Centiloid [CL]) burden was available for all participants, and regression models determined if PRS were associated with CL burden. Results: After harmonization, data for 867 participants showed that high CL burden was most strongly predicted by CSF Aβ42 PRS compared to traditional AD susceptibility PRS. Discussion: This work emphasizes the importance of data harmonization and pooling of cohorts for large-powered studies. Findings suggest a genetic predisposition to amyloid pathology that may predispose individuals early in the AD continuum. This validates the potential use of PRS in clinical (trial) settings as a non-invasive tool to assess AD risk. Highlights: We developed a robust harmonization pipeline for multi-cohort genotype array data. Cerebrospinal fluid amyloid beta (Aβ)-specific polygenic risk scores (PRS) more strongly predicted global Aβ positron emission tomography burden than other PRS. Results suggest a strong genetic predisposition to early Aβ pathology. This work highlights the need for robust data harmonization and data pooling. This work also validates the potential use of PRS as a non-invasive tool to assess Alzheimer's disease risk.
A small molecule stabilizer rescues the surface expression of nearly all missense variants in a GPCR
(Nature Research, 2025) Mighell, Taylor L.; Lehner, Ben, 1978-
Reduced protein abundance is the most frequent mechanism by which rare missense variants cause disease. A promising therapeutic avenue for treating reduced abundance variants is pharmacological chaperones (PCs, also known as correctors or stabilizers), small molecules that bind to and stabilize target proteins. PCs have been approved as clinical treatments for specific variants, but protein energetics suggest their effects might be much more general. To comprehensively assess PC efficacy for variation in a given protein, it is necessary to first assign the molecular mechanism explaining all pathogenic variants, then measure the response to the PC. Here we establish such a framework for the vasopressin 2 receptor (V2R), a G-protein-coupled receptor in which loss-of-function variants cause nephrogenic diabetes insipidus (NDI). Our data show that more than half of NDI variants are poorly expressed, highlighting loss of stability as the major pathogenic mechanism. Treatment with a PC rescues the expression of 87% of destabilized variants. The non-rescued variants identify the drug's predicted binding site. Our results provide proof-of-principle that small molecule binding can rescue destabilizing variants throughout a protein's structure. The application of this principle to other proteins should allow the development of effective therapies for many different rare diseases.
BMAL1-TRIM28 represses transposable elements independently of CLOCK in pluripotent cells
(Nature Research, 2025) Gallardo, Amador; Belmonte-Reche, Efres; Marti-Marimon, María; Domingo-Reinés, Joan; Peris, Guillermo; López-Onieva, Lourdes; Fernández-Rengel, Iván; Xie, Jiajun; Tristán-Ramos, Pablo; Bellora Pereyra, Nicolás; Sánchez-Pozo, Antonio; Estévez, Antonio M.; Heras, Sara R.; Marti-Renom, Marc A.; Landeira, David
Circadian oscillations of gene transcripts rely on a negative feedback loop executed by the activating BMAL1-CLOCK heterodimer and its negative regulators PER and CRY. Although circadian rhythms and CLOCK protein are mostly absent during embryogenesis, the lack of BMAL1 during prenatal development causes an early aging phenotype during adulthood, suggesting that BMAL1 performs an unknown non-circadian function during organism development that is fundamental for healthy adult life. Here, we show that BMAL1 interacts with TRIM28 and facilitates H3K9me3-mediated repression of transposable elements in naïve pluripotent cells, and that the loss of BMAL1 function induces a widespread transcriptional activation of MERVL elements, 3D genome reorganization and the acquisition of totipotency-associated molecular and cellular features. We propose that during embryogenesis, BMAL1 is redeployed as a transcriptional repressor of transposons in a CLOCK-independent way, and the activity of BMAL1-TRIM28 during prenatal life might protect mammalian organisms from premature aging during adulthood.
RNA-binding proteins mediate the maturation of chromatin topology during differentiation
(Nature Research, 2025) Dehingia, Bondita; Severino, Jacqueline, 1990-; Pękowska, Aleksandra
Topologically associating domains (TADs) and chromatin architectural loops impact promoter-enhancer interactions, with CCCTC-binding factor (CTCF) defining TAD borders and loop anchors. TAD boundaries and loops progressively strengthen upon embryonic stem (ES) cell differentiation, underscoring the importance of chromatin topology in ontogeny. However, the mechanisms driving this process remain unclear. Here we show a widespread increase in CTCF-RNA-binding protein (RBP) interactions upon ES to neural stem (NS) cell differentiation. While dispensable in ES cells, RBPs reinforce CTCF-anchored chromatin topology in NS cells. We identify Pantr1, a non-coding RNA, as a key facilitator of CTCF-RBP interactions, promoting chromatin maturation. Using acute CTCF degradation, we find that, through its insulator function, CTCF helps maintain neuronal gene silencing in NS cells by acting as a barrier to untimely gene activation during development. Altogether, we reveal a fundamental mechanism driving developmentally linked chromatin structural consolidation and the contribution of this process to the control of gene expression in differentiation.
Dietary consumption of Type 2 resistant starch and d-fagomine delays progression of metabolic disturbances in male rats on high-fat diet
(Wiley, 2025) Miralles-Pérez, Bernat; Ramos-Romero, Sara; Charpentier, María José; Sánchez-Martos, Vanessa; Fortuño-Mar, Àngels; Ponomarenko, Julia; Amézqueta, Susana; Piñol-Piñol, David; Zhang, Xiang; Torres, Josep Lluís; Romeu, Marta
High-fat (HF) diets contribute to obesity, insulin resistance, fatty liver, gut microbiota dysbiosis, oxidative stress, and low-grade chronic inflammation. This study evaluated the preventive effects of dietary Type 2 resistant starch (RS2) from high-amylose maize and low-dose d-fagomine (FG) from buckwheat on these metabolic disturbances. Male Wistar-Kyoto rats (9-10 weeks old) were assigned to four diet groups for 10 weeks: standard (STD) diet, HF diet (45% kcal from fat), HF + RS diet (15% RS2), and HF + FG diet (0.1% FG). Body characteristics, metabolic parameters, oxidative stress, gut microbiota, short-chain fatty acids (SCFAs), and eicosanoids were analyzed. Both HF + RS and HF + FG diets reduced perigonadal fat, plasma triacylglycerols, and oxidative stress. HF + RS diet improved glucose tolerance without significantly affecting insulin sensitivity, while HF + FG diet showed a tendency for improvement at later stages. Additionally, HF + RS diet showed greater beneficial effects on body weight and liver steatosis than HF + FG diet, likely due to gut microbiota and SCFA modulation. RS2 exerted stronger metabolic effects than FG under HF diet conditions, suggesting its greater potential in mitigating obesity-related complications. FG effects may require longer exposure to manifest.
Astrocytopathy is associated with CA1 synaptic dysfunction in a mouse model of Down syndrome
(MDPI, 2025) Fernández-Blanco, Álvaro; González-Arias, Candela; Sierra, Cesar; Zamora Moratalla, Alfonsa; Perea, Gertrudis; Dierssen, Mara
Brain pathophysiology in Down syndrome (DS), the most common genetic cause of intellectual disability, has traditionally been considered a consequence of neuronal dysfunction. However, although it is well documented that astrocytes play a critical role in brain homeostasis, synaptic regulation, and neuronal support, and their malfunction has been associated with the onset and progression of different neurological disorders, only a few studies have addressed whether astrocyte dysfunction can contribute to the DS pathophysiology. Astrocytes are increased in number and size, and show increased levels of expression of astroglial markers like S100ß and GFAP. In this study, we detected a region-specific increase in astrocyte population in CA1 and, to a lesser extent, in the dentate gyrus. Single-nucleus transcriptomic profiling identified markers associated with reactive astroglia, synaptic transmission, and neuroinflammation in trisomic astrocytes. Functional analysis revealed abnormal Ca2+ oscillations in trisomic astrocytes and impaired astrocyte-to-neuron communication in CA1, the most affected subregion, leading to astrocyte-mediated excitatory synaptic depression. Our findings demonstrate that astrocytes play an active and critical role in the pathophysiology of DS, not only as reactive responders to neuronal injury but as key contributors to the disease process itself. This astrocytic dysfunction presents a region-specific distribution within the hippocampus, suggesting localized vulnerability and complex glial involvement in DS-related neuropathology.
MTHFD2 in healthy and cancer cells: Canonical and non-canonical functions
(Nature Research, 2024) Pardo Lorente, Natalia; Sdelci, Sara
Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial enzyme of the folate-mediated one-carbon metabolism pathway. MTHFD2 has become a highly attractive therapeutic target due to its consistent upregulation in cancer tissues and its major contribution to tumor progression, although it also performs vital functions in proliferating healthy cells. Here, we review the diversity of canonical and non-canonical functions of this key metabolic enzyme under physiological conditions and in carcinogenesis. We provide an overview of its therapeutic potential and describe its regulatory mechanisms. In addition, we discuss the recently described non-canonical functions of MTHFD2 and the mechanistic basis of its oncogenic function. Finally, we speculate on novel therapeutic approaches that take into account subcellular compartmentalization and outline new research directions that would contribute to a better understanding of the fundamental roles of this metabolic enzyme in health and disease.
The proteostatic landscape of healthy human oocytes
(EMBO Press, 2025) Zaffagnini, Gabriele; Solé, Miquel; Duran, Juan M.; Polyzos, Nikolaos P.; Böke, Elvan
Oocytes, female germ cells that develop into eggs, are among the longest-lived cells in the animal body. Recent studies on mouse oocytes highlight unique adaptations in protein homeostasis (proteostasis) within these cells. However, the mechanisms of proteostasis in human oocytes remain virtually unstudied. We present the first large-scale study of proteostatic activity in human oocytes using over 100 freshly donated oocytes from 21 healthy women aged 19-34 years. We analysed the activity and distribution of lysosomes, proteasomes, and mitochondria in both immature and mature oocytes. Notably, human oocytes exhibit nearly twofold lower proteolytic activity than surrounding somatic cells, with further decreases as oocytes mature. Oocyte maturation is also coupled with lysosomal exocytosis and a decrease in mitochondrial membrane potential. We propose that reduced organelle activity preserves key cellular components critical for early embryonic development during the prolonged maturation of human oocytes. Our findings highlight the distinctive biology of human oocytes and the need to investigate human-specific reproductive biology to address challenges in female fertility.
Dysregulated microRNAs in blood correlate with central nervous system neuropathology of prion disease
(BioMed Central, 2025) Pérez-Lázaro, Sonia; Martín-Burriel, Inmaculada; Cozzuto, Luca; Ponomarenko, Julia; Badiola, Juan J.; Bolea, Rosa; Toivonen, Janne M.
The role of microRNAs (miRNAs) in neurodegenerative diseases has gained significant attention because of their involvement in gene regulation and potential as biomarkers. In prion diseases, including scrapie, miRNAs may modulate pathogenesis and disease progression. This study investigated circulating miRNA profiles in the blood of sheep naturally affected by scrapie at preclinical and clinical stages using small RNA sequencing and RT-qPCR validation. While only one novel miRNA was dysregulated in preclinical blood samples, 66 previously annotated miRNAs were significantly dysregulated in clinical sheep compared with healthy sheep. These miRNAs are associated with pathways commonly altered in neurodegenerative diseases, such as autophagy, ubiquitin-mediated proteolysis, and endoplasmic reticulum protein processing. Notably, miR-1271-5p, let-7f-5p, miR-186-5p, and miR-425-5p were consistently upregulated in the central nervous system of clinical animals, replicating the results observed in blood, with an increasing trend already in the preclinical stage and a strong correlation with neuropathological prion features. Additionally, predicted target genes such as UBQLN2, PGK1, KRAS, and CLTC were inversely expressed relative to these miRNAs, supporting their regulatory roles. These findings highlight the relevance of circulating miRNAs in prion neuropathology and support further research into the specific functional roles of these miRNAs and their predictive capacity for disease progression.
Predicting interacting hotspots for nanobodies' binding using triplets of residues
(Wiley, 2025) Hamdani, Rahma; Cianferoni, Damiano; Reche, Raul; Delgado Blanco, Javier; Serrano Pubull, Luis, 1982-
Protein-protein interactions (PPI) are fundamental to cellular signaling, forming robust networks that govern critical biological processes such as immune response, cell growth, and signal transduction. Nanobody-based therapies have emerged as a key strategy for modulating PPIs, offering exceptional potential due to their high specificity, stability, and ability to access challenging epitopes on PPI interfaces inside cells. The rational design of nanobodies relies mainly on understanding and predicting their binding regions, particularly the residues that contribute the most to the binding energy (binding hotspots). Existing computational methods do not fully provide a scalable solution for hotspot identification in nanobody design, leaving a critical gap in the rational design of these therapeutics. Here, we present a scalable and structure-aware algorithm for hotspot prediction in nanobody design. The algorithm queries a curated database of triplets of interacting residues obtained from ~20,000 non-redundant PDB structures. We showed that these triplets contain structural and energetic information, being able to assess the stability effect of residue variations in protein structures, Pearson R = 0.63 (MSE = 1.58 kcal/mol). More important than effects on stability is the ability of the algorithm to predict binding hotspots of protein-protein generic complexes and more specifically in complexes containing nanobodies. HotspotPred reached an accuracy of 0.73 for hotspot residue identification in a protein interaction dataset of 1160 Alanine mutants and correctly identified in 63.4% of the cases we predicted at least 2 residues on the binding surface.
Comparative single-cell analyses reveal evolutionary repurposing of a conserved gene programme in bat wing development
(Nature Research, 2025) Schindler, Magdalena; Barclay, Alexander; Marti-Renom, Marc A.; Real, Francisca M.
Bats are the only mammals capable of self-powered flight, an evolutionary innovation based on the transformation of forelimbs into wings. The bat wing is characterized by an extreme elongation of the second to fifth digits with a wing membrane called the chiropatagium connecting them. Here we investigated the developmental and cellular origin of this structure by comparing bat and mouse limbs using omics tools and single-cell analyses. Despite the substantial morphological differences between the species, we observed an overall conservation of cell populations and gene expression patterns including interdigital apoptosis. Single-cell analyses of micro-dissected embryonic chiropatagium identified a specific fibroblast population, independent of apoptosis-associated interdigital cells, as the origin of this tissue. These distal cells express a conserved gene programme including the transcription factors MEIS2 and TBX3, which are commonly known to specify and pattern the early proximal limb. Transgenic ectopic expression of MEIS2 and TBX3 in mouse distal limb cells resulted in the activation of genes expressed during wing development and phenotypic changes related to wing morphology, such as the fusion of digits. Our results elucidate fundamental molecular mechanisms of bat wing development and illustrate how drastic morphological changes can be achieved through repurposing of existing developmental programmes during evolution.
Structural variation in 1,019 diverse humans based on long-read sequencing
(Nature Research, 2025) Schloissnig, Siegfried; Sotelo-Fonseca, Jesus Emiliano; Moreira Pinhal, Ricardo; Cáceres Aguilar, Mario; Rodríguez Martín, Bernardo; Korbel, Jan O.
Genomic structural variants (SVs) contribute substantially to genetic diversity and human diseases1-4, yet remain under-characterized in population-scale cohorts5. Here we conducted long-read sequencing6 in 1,019 humans to construct an intermediate-coverage resource covering 26 populations from the 1000 Genomes Project. Integrating linear and graph genome-based analyses, we uncover over 100,000 sequence-resolved biallelic SVs and we genotype 300,000 multiallelic variable number of tandem repeats7, advancing SV characterization over short-read-based population-scale surveys3,4. We characterize deletions, duplications, insertions and inversions in distinct populations. Long interspersed nuclear element-1 (L1) and SINE-VNTR-Alu (SVA) retrotransposition activities mediate the transduction8,9 of unique sequence stretches in 5' or 3', depending on source mobile element class and locus. SV breakpoint analyses point to a spectrum of homology-mediated processes contributing to SV formation and recurrent deletion events. Our open-access resource underscores the value of long-read sequencing in advancing SV characterization and enables guiding variant prioritization in patient genomes.

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