Biology subjects

Fontana, L.

Publications and source records attributed to Fontana, L..

6 recordsLinked to original sources

bioRxiv2026

Antibody Correlates of Resilience to Staphylococcus aureus Disease and Recurrence in Children

Staphylococcus aureus remains a major global pathogen with no licensed vaccine and high recurrent infection burden, yet correlates of protection remain undefined. In a prospective pediatric cohort, we profiled 319 children spanning non-carriers, asymptomatic carriers, those with skin and soft tissue infection (SSTI), or invasive disease. We interrogated 182,149 antibody features, generating the most comprehensive S. aureus immune profiling dataset to date. Antibody responses increased with age, marked by expansion of IgG subclasses and Fc-receptor engagement. Asymptomatic carriage was associated with functional antibody profiles targeting conserved surface antigens and select toxins. Multivariate modeling robustly distinguished clinical phenotypes and identified high-value antigens associated with disease resilience. Protection from recurrent disease converged on enhanced Fc{gamma}R binding and antibody effector function. These findings nominate key antigen targets, and highlight anti-Hla neutralizing antibodies and functional antibodies to additional surface antigens that can be recapitulated through Fc engineering, informing next-generation vaccine and monoclonal antibody strategies.

immunology↗

bioRxiv2025

Social and ecological factors associated with innovation in urban sulphur-crested cockatoos (Cacatua galerita)

Why some species thrive in urban environments while others do not is a central question in behavioral ecology. Behavioral innovations has been proposed as a key mechanism facilitating this adaptation. At the individual level, innovativeness varies with cognitive and behavioral traits. However, at the population level, innovation rates can also be influenced by social and ecological factors including group size, and environmental novelty and complexity. The role of these factors are still under-explored, especially at within-city scales. To disentangle factors influencing group-level variation in innovation rates, we presented roosts of wild sulphur-crested cockatoos Cacatua galerita, with extractive-foraging tasks that required innovative problem-solving. We installed three tasks of different levels of difficulty on trees at fifteen communal roost sites across an urban matrix. We matched these with direct measures of roost-size and connectivity, and with high-resolution remote-sensing mapping to estimate variation in urbanization and environmental heterogeneity. We found that approach time was significantly associated with urbanization, with individuals in more urban sites approaching tasks more quickly, suggesting reduced neophobia with urbanization or increased familiarity with human-derived objects. In contrast, time to innovate in our study was explained by task difficulty rather than environmental and social factors. While we detected no significant effects of group size, connectivity, and environmental heterogeneity, larger sample sizes may be needed to reveal more subtle influences on innovation. Together, these results suggest that urbanization gradients can shape behavioral responses to novelty independently from problem-solving abilities. Lay SummaryCities are challenging places for wildlife, but some species, like sulphur-crested cockatoos, adapt by finding new ways to feed and solve problems. We studied how urbanization and social factors vary with cockatoos ability to innovate when presented with extractive-foraging tasks. We found that birds in more urban areas approached the tasks more quickly, suggesting reduced neophobia or increased familiarity with novel objects. This work highlights behavioral differences across urbanization gradients in human-dominated environments.

animal behavior and cognition↗

bioRxiv2025

To preen or not to preen: social predictors of allopreening in a wild parrot

Allogrooming is fundamental to social relationships in many group-living mammals. In primates, allogrooming has been the subject of decades of research, and has been shown to play an essential role in maintaining social affiliations, and often interchanged for social tolerance and support. Yet, while the equivalent behaviour of allopreening occurs in many avian species, most description has been limited to its role in pair formation and maintenance, with little known about non-pair contexts. Here we investigated the decision-making associated with allopreening in wild sulphur-crested cockatoos, conducting detailed observations of 182 allopreening events between 126 individuals while concurrently recording rank, aggressive interactions, and social networks. We found no influence of sex as predicted if allopreening was primarily about pair bonding, but instead a positive correlation between allopreening and aggression (given and received). Within interactions, individuals were influenced by social association strength and rank, with individuals preening for longer and with more turn-taking when interacting with stronger social associates, and individuals investing more in interactions initiated by higher-ranked individuals. Our results are highly suggestive that allopreening may serve a convergent function in wild parrots to primates, both in maintaining social bonds and in negotiating social tolerance.

animal behavior and cognition↗

bioRxiv2025

Metabolic reprogramming and altered ATP content impair neuroprotective functions of microglia in β-glucocerebrosidase deficiency models

Mutations in the GBA gene, which reduce {beta}-glucocerebrosidase (GCase) activity, represent the most significant genetic risk factor for Parkinsons disease (PD). Decreased GCase activity has also been observed in sporadic PD cases, supporting a broader role for GCase in the poorly understood mechanisms underlying PD etiopathogenesis. While most studies on the relationship between GBA mutations and PD have focused on neurons, evidence suggests that PD pathology promoted by GCase deficiency involves other cell types and, in particular, interactions between neuronal and glial cells. Here, we identify microglia as primary players undergoing significant alterations at early stages of the pathological processes triggered by a GCase impairment. Using both pharmacological and genetic mouse models of GCase deficiency, we observed microglial morphological, transcriptional and metabolic changes. Interestingly, these changes were associated with a cell-specific, significant reduction of microglial ATP levels. When microglial ATP depletion was reproduced in an in vitro system of co-cultured microglial and neuronal cells, the neuroprotective properties of microglia were compromised and neuronal susceptibility to oxidative stress was enhanced. These findings underscore the role of microglia in PD pathogenesis and point to a pathogenetic mechanism by which microglial metabolic disturbances leading to ATP depletion enhance neuronal vulnerability to injury and neurodegeneration. This mechanism could be targeted for therapeutic intervention aimed at mitigating PD risk and counteracting the development of PD pathology. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/656111v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@dfd3d7org.highwire.dtl.DTLVardef@ccf2c2org.highwire.dtl.DTLVardef@155d241org.highwire.dtl.DTLVardef@15ed00a_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Multiplex base editing of BCL11A regulatory elements to treat sickle cell disease

Sickle cell disease (SCD) is a genetic anemia caused by the production of an abnormal adult hemoglobin. The clinical severity is lessened by elevated fetal hemoglobin (HbF) production in adulthood. A promising therapy is the transplantation of autologous, hematopoietic stem/progenitor cells (HSPCs) treated with CRISPR/Cas9 to downregulate the HbF repressor BCL11A via generation of double strand breaks (DSBs) in the +58-kb erythroid-specific enhancer. Here, to further enhance HbF production without increasing the mutagenic load, we targeted both +58-kb and +55-kb BCL11A erythroid-specific enhancers using base editors. We systematically dissected DNA motifs recognized by the key transcriptional activators within these regions and identified the critical nucleotides required for activator binding. Multiplex base editing of these residues was efficient and safe and generated no or little DSBs and genomic rearrangements. We observed substantial HbF reactivation, exceeding the levels achieved using the CRISPR/Cas9 nuclease-based strategy, thus efficiently rescuing the sickling phenotype. Multiplex base editing was efficient in long-term repopulating HSPCs and resulted in potent HbF reactivation in vivo. In summary, these results show that multiplex base editing of BCL11A erythroid-specific enhancers is a safe and potent strategy for treating sickle cell disease.

molecular biology↗

bioRxiv2020

Downregulation of miR-17-92 cluster by PERK fine-tunes unfolded protein response mediated apoptosis

An important event in the unfolded protein response (UPR) is the activation of the endoplasmic reticulum kinase PERK (EIF2AK3). The PERK signalling branch first mediates a prosurvival response, which switches into a proapoptotic response upon prolonged ER stress. However, the molecular mechanisms of PERK-mediated cell death are not well understood. Here we show that expression of the primary miR-17-92 transcript and mature miRNAs belonging to miR-17-92 cluster is decreased during UPR. We found that activity of miR-17-92 promoter reporter was reduced during UPR in a PERK-dependent manner. We show that activity of miR-17-92 promoter is repressed by ectopic expression of ATF4 and NRF2. The promoter deletion analysis and ChIP assays mapped the region responding to UPR-mediated repression to site in the proximal region of the miR-17-92 promoter. Hypericin-mediated photo-oxidative ER damage reduced the expression of miRNAs belonging to miR-17-92 cluster in wild-type but not in PERK-deficient cells. Importantly, ER stress-induced apoptosis was inhibited upon miR-17-92 overexpression in SH-SY5Y and H9c2 cells. Our results reveal a novel function for NRF2, where repression of miR-17-92 cluster by NRF2 plays an important role in ER stress-mediated apoptosis. The data presented here provides mechanistic details how sustained PERK signalling via NRF2 mediated repression of miR-17-92 cluster can potentiate cell death.

cell biology↗