Biology subjects

Ferretti, P.

Publications and source records attributed to Ferretti, P..

8 recordsLinked to original sources

bioRxiv2026

Reduced PDE4D expression and activity in Acrodysostosis Type 2 patient fibroblasts underlie disease pathology

BackgroundAcrodysostosis type 2 (ACRDYS2) is a rare autosomal dominant disease characterized by skeletal defects and cognitive deficit, with clinical symptoms observed in multiple other tissues including the skin. It is caused by mutations in a phosphodiesterase, PDE4D, a key regulator of cAMP/PKA (cyclic adenosine monophosphate / protein kinase A) signalling. Despite its well-defined genetic causes, the molecular mechanisms underlying the disease remain poorly understood, with studies based largely on engineered cellular models reaching conflicting interpretations. MethodsTo investigate how endogenous dynamics are affected by PDE4D mutations in unmanipulated cells, we studied PDE4D transcript and protein expression, activity and downstream signalling in native dermal fibroblast from ACRDYS2 patients and healthy controls. ResultsSignificant reduction in total PDE4D expression in patient cells was observed both at the transcript and protein level, with marked decreases in the long isoforms PDE4D4 and PDE4D7; a reduction in PDE4D9 mRNA was also observed. PDE4D enzymatic activity was reduced in ACRDYS2 fibroblasts, though total PDE activity was largely preserved. Reduced PDE4D expression was associated with an increase in the phosphorylated form of the cAMP-responsive transcription factor CREB and elevated PRKAR1A (PKA type 1 regulatory subunit alpha) transcript levels, suggesting altered downstream signalling. Interestingly, expression of the related phosphodiesterase family member PDE4B was increased, consistent with a compensatory response to reduced PDE4D function. ConclusionsThis is the first study demonstrating reduced PDE4D expression and isoform-specific dysregulation in native ACRDYS2 cells. Together, our results support a model in which reduction in PDE4D activity and compensatory changes in other PDE4 family members contribute to the molecular pathology of ACRDYS2, providing new insights into the molecular mechanisms underlying this disorder.

cell biology↗

bioRxiv2026

Social microbiome transmission predicts microbial specialization and host lifespan in a wild primate

Social interactions are proposed to provide reliable routes for microbial transmission between animals, facilitating animal-microbiome co-evolution. However, microbiome transmission remains challenging to measure in wild populations. Here we combine behavioral observations of wild baboons with repeated strain-resolved metagenomic profiling to identify individual gut microbial species that follow a dominant mode of social transmission. In an 18-year metagenomic time series from the same population, baboons with higher levels of socially transmitted species lived longer than those with lower levels of socially transmitted species. Socially transmitted species were also more stable and persistent within baboons, yet had narrower host ranges outside of baboons. Thus, social transmission is not only detectable in free-living primates, but may play a special role in both host and microbial fitness.

evolutionary biology↗

bioRxiv2025

Demographic, behavioral, and ecological data from a long-term field study of wild baboons in Amboseli, Kenya

Long-term data sets on individually recognized animals and their environments are critical to understanding animal behavior, evolution, and ecology. However, they are resource- and time-intensive and seldom made publicly available. The Amboseli Baboon Research Project (ABRP) is one of the longest-running studies of a wild mammal population in the world and has collected extensive data on the baboon population of the Amboseli ecosystem in Kenya since 1971. Here, we describe four ABRP data sets newly available to the evolutionary biology, behavioral ecology, and primatology communities: (1) the sizes and demographic compositions of 21 social groups from 1971-2023; (2) the activity budgets of adult females and immatures from 1984-2023; (3) behavioral data on diet for adult females and immatures from 1984-2023; and (4) weather data, including precipitation from 1976-2023 and temperature from 1976-2022. Data are aggregated annually and monthly to enable cross-data set analyses. These data offer a rare longitudinal perspective on behavioral and ecological change in a wild mammal population.

animal behavior and cognition↗

bioRxiv2025

Metalog: curated and harmonised contextual data for global metagenomics samples

Metagenomic sequencing enables the in-depth study of microbes and their functions in humans, animals and the environment. While sequencing data is deposited in public databases, the associated contextual data is often not complete and needs to be retrieved from primary publications. This lack of access to sample-level metadata like clinical data or in situ observations impedes cross-study comparisons and meta-analyses. We therefore created the Metalog database, a repository of manually curated metadata for metagenomics samples across the globe. It contains 73,082 samples from humans (including 58,506 of the gut microbiome), 10,703 animal samples, 5,146 ocean water samples, and 21,802 samples from other environmental habitats such as soil, sediment, or fresh water. Samples have been consistently annotated for a set of habitat-specific core features, such as demographics, disease status and medication for humans, host species and captivity status for animals, and filter sizes and salinity for marine samples. Additionally, all original metadata is provided in tabular form, simplifying focused studies e.g. into nutrient concentrations. Pre-computed taxonomic profiles facilitate rapid data exploration, while links to the SPIRE database enable genome-based analyses. The database is freely available for browsing and download at https://metalog.embl.de/.

microbiology↗

bioRxiv2024

A comprehensive spatiotemporal map of dystrophin isoform expression in the developing and adult human brain

Mutations in the dystrophin gene (DMD) cause the severe muscle-wasting disease Duchenne Muscular Dystrophy (DMD). Additionally, there is a high incidence of intellectual disability and neurobehavioural comorbidities in individuals with DMD. Similar behavioural abnormalities are found in mdx dystrophic mouse models. Unlike muscle, several dystrophin isoforms are expressed in the human brain, but a detailed map of regional and cellular localisation of dystrophin isoforms is missing. This is crucial in understanding the neuropathology of DMD individuals, and for evaluating the translatability of pre-clinical findings in DMD mouse models receiving genetic therapy interventions. Here, we provide a comprehensive dystrophin expression profile in human brains from early development to adulthood. We reveal expression of dp427p2, dp427c, dp427m and dp40 isoforms in embryonic brains, not previously reported. Dp427p2 and dp140 were greatly downregulated in adult brains, although the latter continued to be expressed across several regions. Importantly, we demonstrate for the first-time expression of DMD transcripts in human motor neurons and co-expression of different dystrophin isoforms within single neurons in both developing and adult brains. Finally, we show localisation of DMD transcripts with GAD1+ GABAergic-associated transcripts in neurons including cerebellar Purkinje cells and interneurons, as well as in the majority of neocortical and hippocampal SLC17A7+ glutamatergic neurones, suggesting a role for dystrophin in signalling at the neuronal inhibitory and excitatory synapses. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=178 HEIGHT=200 SRC="FIGDIR/small/629620v1_ufig1.gif" ALT="Figure 1"> View larger version (70K): org.highwire.dtl.DTLVardef@1dda96corg.highwire.dtl.DTLVardef@19e133corg.highwire.dtl.DTLVardef@100e8c5org.highwire.dtl.DTLVardef@b1ef77_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Fecal microbial load is a major determinant of gut microbiome variation and a confounder for disease associations

The microbiota in individual habitats differ both in relative composition and absolute abundance. While sequencing approaches determine only the relative abundances of taxa and genes, experimental techniques for absolute abundance determination are rarely applied to large-scale microbiome studies. Here, we developed a machine learning approach to predict fecal microbial loads (microbial cells per gram) solely from relative abundance data. Applied to large-scale datasets (n = 34,539), we demonstrate that microbial load is the major determinant of gut microbiome variation and associated with numerous host factors. We found that for several diseases, the altered microbial load, not the disease itself, was the main driver of the gut microbiome changes. Adjusting for this effect substantially reduced the significance of more than half of the disease-associated species. Our analysis reveals that the fecal microbial load is a major confounder in microbiome studies, highlighting its importance for understanding microbiome variation in health and disease.

microbiology↗

bioRxiv2024

Assembly, stability, and dynamics of the infant gut microbiome are linked to bacterial strains and functions in mother's milk

The establishment of the gut microbiome in early life is critical for healthy infant development. Although human milk is recommended as sole nutrition for the infant, little is known about how variation in the milk microbiome shapes the microbial communities in the infant gut. Here, we quantified the similarity between the maternal milk and the infant gut microbiome using 507 metagenomic samples collected from 195 mother-infant pairs at one, three, and six months postpartum. Microbial taxonomic overlap between milk and the infant gut was driven by Bifidobacterium longum, and infant microbiomes dominated by B. longum showed greater temporal stability than those dominated by other species. We identified numerous instances of strain sharing between milk and the infant gut, involving both commensal (e.g. B. longum) and pathobiont species (e.g. K. pneumoniae). Shared strains also included typically oral species such as S. salivarius and V. parvula, suggesting possible transmission from the infants oral cavity to the mothers milk. At one month, the infant gut microbiome was enriched in biosynthetic pathways, suggesting that early colonisers might be more metabolically independent than later ones. Lastly, we observed significant overlap in antimicrobial resistance gene carriage within mother-infant pairs. Together, our results suggest that the human milk microbiome has an important role in the assembly, composition, and stability of the infant gut microbiome.

microbiology↗

bioRxiv2022

C. difficile is overdiagnosed in adults and a commensal in infants

Clostridioides difficile is an urgent threat in hospital-acquired infections world-wide, yet the microbial composition associated with C. difficile, in particular in C. difficile infection (CDI) cases, remains poorly characterised. To investigate the gut microbiome composition in CDI patients, we analysed 534 metagenomes from 10 publicly available CDI study populations. We then tracked C. difficile on a global scale, screening 42,900 metagenomes from 253 public studies. Among the CDI cohorts, we detected C. difficile in only 30% of the stool samples from CDI patients. However, we found that multiple other toxigenic species capable of inducing CDI-like symptomatology were prevalent. In addition, the majority of the investigated studies did not adhere to the recommended guidelines for a correct CDI diagnosis. In the global survey, we found that C. difficile prevalence, abundance and biotic context were age-dependent. C. difficile is a rare taxon associated with reduced diversity in healthy adults, but common and associated with increased diversity in infants. We identified a group of species co-occurring with C. difficile exclusively in healthy infants, enriched in obligate anaerobes and in species typical of the healthy adult gut microbiome. C. difficile in healthy infants was therefore associated with multiple indicators of healthy gut microbiome maturation. Our analysis raises concerns about potential CDI overdiagnosis and suggests that C. difficile is an important commensal in infants and that its asymptomatic carriage in adults depends on microbial context.

microbiology↗