Biology subjects

Brancaccio, A.

Publications and source records attributed to Brancaccio, A..

6 recordsLinked to original sources

bioRxiv2026

TIDE: Tractography-Informed Dose Estimation for individualised TMS intensity

Transcranial magnetic stimulation (TMS) is commonly dosed by setting stimulation intensity as a fixed percentage of the resting motor threshold (RMT), although a motor-derived intensity may not produce comparable neural recruitment across non-motor targets. We present TIDE (Tractography-Informed Dose Estimation), an open-source, SimNIBS-based pipeline designed to derive individualised stimulation intensities for non-motor white-matter targets. TIDE combines individual RMT measurements, finite-element electric-field modelling and diffusion MRI tractography to rescale the stimulation intensity according to the geometry and stimulation efficiency of the pathway of interest. Specifically, it computes the activating function along subject-specific streamlines and estimates the stimulator output, expressed as a percentage of maximum stimulator output, required for the target pathway to reach the activation level produced in the corticospinal tract at RMT. In an independent dataset of 19 participants, in which stimulation had been dosed conventionally as a fixed percentage of RMT, the relative difference between delivered and TIDE-estimated intensity was associated with the magnitude of TMS-induced behavioural effects at two frontal aslant tract (FAT) stimulation sites, while the delivered intensity alone was not. TIDE therefore extends conventional E-field dosing from cortical field magnitude to subject-specific pathway geometry, providing a method to move beyond the assumption of homogeneous pathway engagement while accounting for inter-individual variability in pathway-specific stimulation efficiency.

neuroscience↗

bioRxiv2024

Fully Hyperbolic Neural Networks: A Novel Approach to Studying Aging Trajectories

Characterizing age-related alterations in brain networks is crucial for understanding aging trajectories and identifying deviations indicative of neurodegenerative disorders, such as Alzheimers disease. In this study, we developed a Fully Hyperbolic Neural Network (FHNN) to embed functional brain connectivity graphs derived from magnetoencephalography (MEG) data into low dimensions on a Lorentz model of hyperbolic space. Using this model, we computed hyperbolic embeddings of the MEG brain networks of 587 individuals from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) dataset. Notably, we leveraged a unique metric--the radius of the node embeddings--which effectively captures the hierarchical organization of the brain, to characterize subtle hierarchical organizational changes in various brain subnetworks attributed to the aging process. Our findings revealed that a considerable number of subnetworks exhibited a reduction in hierarchy during aging, with some showing gradual changes and others undergoing rapid transformations in the elderly. Moreover, we demonstrated that hyperbolic features outperform traditional graph-theoretic measures in capturing age-related information in brain networks. Overall, our study represents the first evaluation of hyperbolic embeddings in MEG brain networks for studying aging trajectories, shedding light on critical regions undergoing significant age-related alterations in the large cohort of the Cam-CAN dataset.

bioinformatics↗

bioRxiv2023

A missense mutation (C667F) in beta-dystroglycan results in reduced dystroglycan protein levels leading to myopathy and destabilization of the blood-brain and blood-retinal barrier protein network

Dystroglycan (DG) is a glycoprotein and extracellular matrix receptor consisting of an -DG and a {beta}-DG subunit encoded by the gene DAG1. A homozygous missense mutation (c.2006G>T), resulting in an amino acid substitution (p.Cys669Phe) in the extracellular domain of {beta}-DG, causes severe Muscle-Eye-Brain disease with multicystic leukodystrophy. To investigate the mechanisms underlying the severe human pathology, we generated a mouse model of this primary dystroglycanopathy. We find that homozygous mutant mice show no obvious abnormalities during development and reach mature adulthood. However, - and {beta}-DG protein levels are significantly downregulated in muscle and brain of homozygous mutant mice. The mutant mice show a form of myopathy with late-onset and not fully penetrant histopathological changes in skeletal muscle and are impaired in their performance on an activity wheel. The brain and eyes of the homozygous mutant mice appear to be structurally normal, but the localization of mutant {beta}-DG is altered in the glial perivascular endfeet (PVE) at the blood-brain- and blood-retina barrier resulting in a perturbed protein composition in the PVE. In conclusion, the mouse model of the C669F {beta}-DG mutation does not seem to recapitulate the severe developmental phenotypes observed in human patients but represents a novel and highly valuable tool to study the impact of {beta}-DG functional changes at the molecular level and to gain insight into the pathogenesis of primary dystroglycanopathies.

pathology↗

bioRxiv2023

The α-dystroglycan N-terminus is a broad-spectrum antiviral agent against SARS-CoV-2 and enveloped viruses

The COVID-19 pandemic has shown the need to develop effective therapeutics in preparedness for further epidemics of virus infections that pose a significant threat to human health. As a natural compound antiviral candidate, we focused on -dystroglycan, a highly glycosylated basement membrane protein that links the extracellular matrix to the intracellular cytoskeleton. Here we show that the N-terminal fragment of -dystroglycan (-DGN), as produced in E. coli in the absence of post-translational modifications, blocks infection of SARS-CoV-2 in cell culture, human primary gut organoids and the lungs of transgenic mice expressing the human receptor angiotensin I-converting enzyme 2 (hACE2). Prophylactic and therapeutic administration of -DGN reduced SARS-CoV-2 lung titres and protected the mice from respiratory symptoms and death. Recombinant -DGN also blocked infection of a wide range of enveloped viruses including the four Dengue virus serotypes, influenza A virus, respiratory syncytial virus, tick-borne encephalitis virus, but not human adenovirus, a non-enveloped virus in vitro. This study establishes soluble recombinant -DGN as a broad-band, natural compound candidate therapeutic against enveloped viruses.

microbiology↗

bioRxiv2023

Region-specific impact of aging on cortical myelination and thickness

Healthy aging affects both grey and white matter. However, the trajectories of regional specific degeneration are not fully understood. Here we investigate the effects of aging on cortical thickness and myelin concentration in a large cohort of healthy participants (N = 610) aged between 18 and 89 years old who underwent single-site T1-weighted, T2-weighted and MTI sequences in the context of the Cam-CAN project. Participants were subdivided in three age groups representative of young, middle and late adulthood. The large size of the dataset allowed us to minimize the impact of sample variance without relying on multi-site acquisition protocols. We assessed linear changes in cortical thickness and cortical myelin concentration; the latter was assessed using both T1w/T2w ratio and MTR proxies, to evaluate which is the most stable metrics. Our results do not fit with either the anterior-posterior gradient or the last-in/first-out hypothesis. We demonstrate that aging patterns are more complex than just depending on a spatial gradient or the temporally reversed order of regional development. Moreover, we show a dissociation in aging patterns between somatosensory and motor regions both in terms of cortical thickness and myelin concentration. Finally, comparing T1w/T2w and MTR results of cortical myelination, we found the latter being a more stable and reliable proxy. HighlightsO_LICortical thickness and myelo-architecture changes must be jointly considered in investigating brain aging trajectories. C_LIO_LIWe assessed linear changes in cortical thickness and myelination in a large, homogeneous and single site MRI dataset. C_LIO_LIMotor and sensory regions show a dissociation in their aging trajectories both in terms of cortical thickness and myelin concentration. C_LIO_LISensory processing regions show similar aging trajectories in both cortical thickness and myelin concentration. C_LIO_LIMTR is a more reliable proxy for myelin concentration compared to T1w/T2w ratio. C_LI

neuroscience↗

bioRxiv2023

Cryo-electron tomography of C. elegans mitochondria reveals how the ATP synthase dimer interface shapes crista membranes

Mitochondrial ATP synthases form rows of dimers, which induce membrane curvature to give cristae their characteristic lamellar or tubular morphology. The angle formed between the central stalks of ATP synthase dimers varies between species. Using cryo-electron tomography and sub-tomogram averaging, we determined the structure of the ATP synthase dimer from the nematode worm C. elegans and show that the dimer angle differs from previously determined structures. The consequences of this species-specific difference at the dimer interface were investigated by comparing C. elegans and S. cerevisiae mitochondrial morphology. We reveal that C. elegans has a larger ATP synthase dimer angle with more lamellar (flatter) cristae when compared to yeast. The underlying cause of this difference was investigated by generating an atomic model of the C. elegans ATP synthase dimer by homology modelling. A comparison of our C. elegans model to an existing S. cerevisiae structure reveals the presence of extensions and rearrangements in C. elegans subunits associated with maintaining the dimer interface. We speculate that increasing dimer angles could provide an advantage for species that inhabit variable-oxygen environments by forming flatter more energetically efficient cristae.

biochemistry↗