Biology subjects

Ferrarini, A.

Publications and source records attributed to Ferrarini, A..

7 recordsLinked to original sources

bioRxiv2025

The Dark Side of Biomolecular Condensates: Quantifying the Role of Nucleic Acids

Liquid-Liquid Phase Separation (LLPS) is being increasingly recognized as a major organizational principle for proteins and nucleic acids (NAs) in cells, as well as a promising strategy for synthetic biology and biomedical applications. Extensive work has explored the role of protein sequence and properties in the regulation of LLPS. On the contrary, the role of nucleic acids has often been overlooked. Here, to fill this gap we focus on model systems made of oligonucleotides with tuned lengths and degree of hybridization, mixed with a moderately charged, disordered peptide. Combining multiple length scales through experiments and molecular dynamics simulations, we unravel the distinct effect of the properties of NAs on the phase behavior and we propose a metric for the stability of biocondensates. We also characterize the conditions for the onset of liquid crystalline order in the droplets and we show that it is associated with a dramatic slowing down of the dynamics of oligonucleotides, while peptides retain high mobility. Our results can be generalized to natural and non-natural NAs of arbitrary structure, providing a guide for the design of synthetic NA-containing coacervates. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/683552v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@179be04org.highwire.dtl.DTLVardef@1aa0192org.highwire.dtl.DTLVardef@4d411aorg.highwire.dtl.DTLVardef@1ed238d_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2025

TurbOmics: a web-based platform for the analysis of metabolomics data using a multi-omics integrative approach

In recent years, multi-omics integration has proven highly effective for the holistic characterization of biological systems, with the development of numerous bioinformatic platforms. However, these tools face limitations when incorporating metabolomics data, including absence of support for untargeted metabolomics annotation and dependence on predefined knowledge bases. Furthermore, the advanced algorithms required for multi-omics integration typically demand programming skills and statistical background, restricting their use to specialized users. To advance towards resolving these challenges, we present TurbOmics, a user-friendly web-based platform that enables researchers with diverse backgrounds to analyze metabolomics, proteomics, and transcriptomics data using advanced algorithms for multi-omics integration, while addressing key challenges associated with metabolomics data. Users can upload quantitative data and include additional information, such as metabolite identification or lipid classes, that streamline the interpretation of complex results. TurbOmics can be used sequentially with our previously published tool, TurboPutative, to simplify, reduce and prioritize the list of putative annotations from untargeted metabolomics datasets. Thanks to its flexible and interactive interface, researchers can perform exploratory data analysis and multi-omics integration using the Multi-Omics Factor Analysis, Pathway Integrative Analysis and Enrichment Analysis modules. We believe that TurbOmics will make multi-omics analysis more accessible to the research community. The platform is freely available at https://proteomics.cnic.es/TurboPutative/TurbOmicsApp.html. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/653072v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@26a2e6org.highwire.dtl.DTLVardef@90bfa8org.highwire.dtl.DTLVardef@116d6e4org.highwire.dtl.DTLVardef@76134b_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO C_FIG

bioinformatics↗

bioRxiv2025

Modeling the acutely injured brain environment in vitro.

A major challenge to study the regenerative potential of the injured brain is the limited access to this organ in vivo. To address this, we developed an innovative gliosis model that, although established in vitro, originates from a genuine injury in vivo. The model relies on reactive glia acquiring enhanced adhesion, facilitating their rapid adaptation to in vitro conditions, where it faithfully recapitulates key features of brain injury. These include a secretome associated with injury pathways, degenerative responses like neuronal death and neuroinflammation, and regenerative processes such as progenitor proliferation, recruitment and commitment to oligodendrocytes. Moreover, the exposure of adult glial cells to this culture medium recapitulates their acquisition of multipotency observed in both mouse and human injured brains. Finally, our approach allows studying glia-to-neuron reprogramming, a process challenging to tackle in vivo. Consequently, we present a novel tool for exploring stem cell dynamics and regenerative behaviors in CNS pathology.

neuroscience↗

bioRxiv2024

Broad therapeutic benefit of myosin inhibition in hypertrophic cardiomyopathy

Myosin inhibitor mavacamten is the only targeted treatment available for hypertrophic cardiomyopathy (HCM), a disease caused by hundreds of genetic variants that affect mainly sarcomeric myosin and its negative regulator cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3). Here, we have examined whether the reported limited efficacy of mavacamten in a fraction of HCM patients can result from dissimilar HCM pathomechanisms triggered by different genetic variants, a scenario particularly relevant for MYBPC3-associated HCM. To this aim, we have generated knock-in mice including missense pathogenic variant cMyBP-C p.R502W, which, different from patients who carry truncations in the protein, develop progressive pathogenic myocardial remodeling in the absence of alterations of cMyBP-C levels and localization. Mechanistically, we find that mutation R502W reduces the binding affinity of cMyBP-C for myosin without inducing a shift towards more active myosin conformations as observed when cMyBP-C levels are reduced. Despite these diverging molecular alterations, we show that mavacamten blunts myocardial remodeling both in R502W and cMyBP-C-deficient, knock-out hearts. These beneficial effects are accompanied by improved tolerance to exercise only in R502W animals. Hence, our results indicate that myosin inhibition is effective to treat HCM caused by both truncating and missense variants in MYBPC3 regardless of the primary pathomechanisms they elicit.

physiology↗

bioRxiv2020

Activation of amino acid metabolic program in response to impaired glycolysis in cardiac HIF1 deficient mice

Hypoxia is an important environmental cue in heart development. Despite of extensive characterization of gain and loss of function models, there is disagreement about the impact of HIF1 elimination in cardiac tissue. Here, we used a new conditional knock out of Hif1a in NKX2.5 cardiac progenitors to assess the morphological and functional consequences of HIF1 loss in the developing heart. By combining histology, electron microscopy and high-throughout genomics, proteomics and metabolomics, we found that deletion of Hif1a leads to impaired embryonic glycolysis without influencing cardiomyocyte proliferation and results in an increased mitochondrial number, activation of a transient amino acid response and upregulation of HIF2 and ATF4 by E12.5. Hif1a mutants display normal fatty acid oxidation metabolic profile and do not show any sign of cardiac dysfunction in the adulthood. Our results demonstrate that HIF1 signaling is dispensable for heart development and reveal the metabolic flexibility of the embryonic myocardium, opening the potential application of alternative energy sources as therapeutic interventions during ischemic events.

developmental biology↗

bioRxiv2019

Metabolic reprogramming from glycolysis to amino acid utilization in cardiac HIF1α deficient mice.

RationaleHypoxia is an important environmental cue implicated in several physiopathological processes, including heart development. Several mouse models of activation or inhibition of hypoxia have been previously described. While gain of function models have been extensively characterized and indicate that HIF1 signaling needs to be tightly regulated to ensure a proper cardiac development, there is lack of consensus in the field about the functional outcomes of HIF1 loss.\n\nObjectiveIn this study, we aim to assess the consequences of cardiac deletion of HIF1 during heart development and identify the cardiac adaptations to HIF1 loss.\n\nMethods and ResultsHere, we used a conditional deletion model of Hif1a in NKX2.5+ cardiac progenitors. By a combination of histology, electron microscopy, massive gene expression studies, proteomics, metabolomics and cardiac imaging, we found that HIF1 is dispensable for cardiac development. Hif1a loss results in glycolytic inhibition in the embryonic heart without affecting normal cardiac growth. However, together with a premature increase in mitochondrial number by E12.5, we found global upregulation of amino acid transport and catabolic processes. Interestingly, this amino acid catabolism activation is transient and does not preclude the normal cardiac metabolic switch towards fatty acid oxidation (FAO) after E14.5. Moreover, Hif1a loss is accompanied by an increase in ATF4, described as an important regulator of several amino acid transporters.\n\nConclusionsOur data indicate that HIF1 is not required for normal cardiac development and suggest that additional mechanisms can compensate Hif1a loss. Moreover, our results reveal the metabolic flexibility of the embryonic heart at early stages of development, showing the capacity of the myocardium to adapt its energy source to satisfy the energetic and building blocks demands to achieve normal cardiac growth and function. This metabolic reprograming might be relevant in the setting of adult cardiac failure.

developmental biology↗

bioRxiv2019

Heterozygous variants in KMT2E cause a spectrum of neurodevelopmental disorders and epilepsy

We delineate a KMT2E gene-related neurodevelopmental disorder based on 38 individuals in 36 families. This includes 31 distinct heterozygous variants in the KMT2E gene (28 ascertained from Matchmaker Exchange and 3 previously reported), and 4 individuals with chromosome 7q22.2-22.23 microdeletions encompassing the KMT2E gene (1 previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants, and was responsive to treatment with anti-epileptic medications in almost all. Over 70% of the individuals were male and expressivity was variable by sex, with epilepsy more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant negative effects specific to these missense variants in KMT2E may explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

genetics↗