Biology subjects

Schiavi, A.

Publications and source records attributed to Schiavi, A..

6 recordsLinked to original sources

bioRxiv2026

Computational Evaluation of tDCS Montage Separability and Dose Coverage for Practice-Specific Mindfulness Experiments

A practice-specific stimulation experiment requires candidate montages that differ in regional electric-field exposure without sacrificing interpretable target dose. We evaluated this requirement for transcranial direct current stimulation (tDCS) montages intended to test focused-attention and open-monitoring mindfulness practices. Four focused-attention candidates and six open-monitoring candidates formed 24 pairs, evaluated with SimNIBS 4.6 in 20 existing anatomical head models at a linearly scaled current of 2 mA. Outcomes were regional 99th-percentile field magnitude, a normalized double-dissociation index (DDI), suprathreshold overlap, and individual dose coverage. Eighteen pairs passed four recorded progression criteria, but only five also met a post hoc requirement that both intended regional contrasts be positive in at least 80% of heads. A positive DDI alone concealed a reversed salience-region contrast in one conventional comparison. The nominated F3-centered 4-by-1 ring paired with F8-Fp2 sponges (FA-05 x OM-02) produced both directional preferences in 20/20 heads, with median DDI 1.561 and median suprathreshold Dice 0.000. The conventional F3-Fp2 and FT8-FCz sponge pair (FA-02 x OM-07) produced both preferences in 19/20 heads, with DDI 0.627 and Dice 0.186. Both anatomical targets reached the operational 0.20 V/m floor in 11/20 versus 20/20 heads, respectively. ROAST 4.0, with ring placement held fixed, supported both nominations but exposed dose disagreement. Across conductivity sensitivity draws, directional separability persisted more consistently than absolute dose. These results establish a regional separability-dose trade-off within the tested candidate set and show why a summed contrast cannot substitute for a directional conjunction. They support selection of a discriminating experiment, not whole-network selectivity, physiological efficacy, or a validated treatment.

neuroscience↗

bioRxiv2025

Mitochondrial redox homeostasis links organellar stress surveillance to germline and somatic integrity in Caenorhabditis elegans

Mitochondrial redox homeostasis is essential for cellular metabolism and organismal development. To investigate the consequences of disrupting redox homeostasis in this organelle in a metazoan organism, we generated a double mutant lacking mitochondrial glutathione reductase (gsr-1a) and thioredoxin reductase (trxr-2) genes in Caenorhabditis elegans. While gsr-1a or trxr-2 single mutants are phenotypically normal, double gsr-1a trxr-2 mutants displayed small body size, gonadal migration defects, reduced brood size, and prolonged egg-laying period, without developmental delay or lethality. Transcriptomic analysis revealed strong induction of ATFS-1-dependent stress and detoxification genes. Consistent with this, gsr-1a trxr-2 worms exhibited constitutive ATFS-1 nuclear localization and robust Phsp-6::gfp expression. Triple gsr-1a trxr-2; atfs-1 mutants were nonviable, demonstrating that unfolded protein response (UPRmt) activation is essential under mitochondrial redox stress. Despite the induction of a stress response at the transcriptional level, gsr-1a trxr-2 double mutants were not more resistant to oxidative or pathogen stressors. Moreover, these mutants maintained normal respiration, ATP and ROS production while displaying altered mitochondrial morphology in a tissue-specific manner, independent of mitophagy genes but dependent on mitochondrial fission or fusion machinery. Functionally, gsr-1a trxr-2 mutants showed impaired motility, reduced calcium uptake upon carbachol stimulation, enhanced hypodermal wound repair, and decreased fertilization efficiency associated with lower muscle exopher production. Overall, our data show that simultaneous loss of mitochondrial GSR-1a and TRXR-2 compromises growth, fertility and muscle performance and triggers a constitutive ATFS-1-dependent UPRmt that sustains viability revealing mitochondrial redox control as a core determinant of organismal proteostasis. HighlightsO_LIgsr-1a or trxr-2 single mutants have no overt phenotypes. C_LIO_LIgsr-1a trxr-2 double mutants are viable but show small size, gonad migration defects and reduced progeny. C_LIO_LILoss of both reductases in mitochondria triggers a constitutive ATFS-1-dependent UPRmt. C_LIO_LIATFS-1 is essential for gsr-1a trxr-2 worms survival. C_LIO_LIgsr-1a trxr-2 animals remodel mitochondrial morphology in a tissue-specific manner. C_LIO_LIgsr-1a trxr-2 double mutants exhibit impaired muscle and sperm function but enhanced wound healing. C_LI Graphical abstract (to be incorporated)

genetics↗

bioRxiv2024

Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain

Mitochondria and lysosomes are two organelles that carry out both signaling and metabolic roles in the cells. Recent evidence has shown that mitochondria and lysosomes are dependent on one another, as primary defects in one cause secondary defects in the other. Nevertheless, the signaling consequences of primary mitochondrial malfunction and of primary lysosomal defects are not similar, despite in both cases there are impairments of mitochondria and of lysosomes. Here, we used RNA sequencing to obtain transcriptomes from cells with primary mitochondrial or lysosomal defects, to identify what are the global cellular consequences that are associated with malfunction of mitochondria or lysosomes. We used these data to determine what are the pathways that are affected by defects in both organelles, which revealed a prominent role for the cholesterol synthesis pathway. This pathway is transcriptionally up-regulated in cellular and mouse models of lysosomal defects and is transcriptionally down-regulated in cellular and mouse models of mitochondrial defects. We identified a role for post-transcriptional regulation of the transcription factor SREBF1, a master regulator of cholesterol and lipid biosynthesis, in models of mitochondrial respiratory chain deficiency. Furthermore, the retention of Ca2+ in the lysosomes of cells with mitochondrial respiratory chain defects contributes to the differential regulation of the cholesterol synthesis pathway in the mitochondrial and lysosomal defects tested. Finally, we verified in vivo, using models of mitochondria-associated diseases in C. elegans, that normalization of lysosomal Ca2+ levels results in partial rescue of the developmental arrest induced by the respiratory chain deficiency.

biochemistry↗

bioRxiv2022

Aryl hydrocarbon receptor-dependent and -independent pathways mediate curcumin anti-aging effects

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor whose activity can be modulated by polyphenols such as curcumin. AhR and curcumin have evolutionarily conserved effects on aging. Here, we investigated whether and how the AhR mediates the anti-aging effects of curcumin across species. Using a combination of in vivo, in vitro, and in silico analyses, we demonstrated that curcumin has AhR-dependent or -independent effects in a context-specific manner. We found that in Caenorhabditis elegans, AhR mediates curcumin-induced lifespan extension, most likely through a ligand-independent inhibitory mechanism related to its antioxidant activity. Curcumin also showed AhR-independent anti-aging activities such as protection against aggregation-prone proteins and oxidative stress in C. elegans and promotion of the migratory capacity of human primary endothelial cells. These AhR-independent effects are largely mediated by the Nrf2/SKN-1 pathway. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/479676v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@15ccf21org.highwire.dtl.DTLVardef@22886eorg.highwire.dtl.DTLVardef@12b211eorg.highwire.dtl.DTLVardef@8b4474_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2020

Ahr-bacterial diet interaction modulates aging and associated pathologies in C. elegans

Genetic and environmental factors concurrently shape the aging process. The nematode Caenorhabditis elegans has been instrumental in the past 30 years to identify most genes and interventions nowadays known to modulate aging (Lopez-Otin et al. 2013, Tigges et al. 2014, Dato et al. 2017). The aryl-hydrocarbon-receptor (AhR) was discovered as a dioxin-binding transcription factor involved in the metabolism of different environmental toxicants and xenobiotics (Poland et al. 1976). Since then, the variety of pathophysiological processes regulated by the AhR has rapidly grown, ranging from the immune response to cell death and metabolic pathways, and we disclosed it promotes aging phenotypes across species (Eckers et al. 2016, Esser et al. 2018). Interestingly, many AhR modulators may impact on aging and age-associated pathologies, but, whether their effects are actually AhR-dependent has never been explored. Here, we show for the first time that lack of C. elegans AHR-1 affects health and lifespan in a context-dependent manner. Using known mammalian AhR modulators we found that, similar to mammals, ahr-1 has protective effects against environmental insults and identified a new role for AhR-bacterial diet interaction in animal lifespan, stress resistance, and age-associated pathologies. We narrowed down the dietary factor involved in the observed AhR-dependent features to a bacterially-extruded metabolite likely involved in tryptophan metabolism. This is the first study clearly establishing C. elegans as a good model organism to investigate evolutionarily conserved functions of AhR-modulators and -regulated processes, indicating it can be exploited to contribute to the discovery of novel information about AhR in mammals. Significance StatementThe roundworm C. elegans has been instrumental for the identification of many of the genetic and environmental factors known to concurrently shape the aging process. The aryl-hydrocarbon-receptor (AhR) was originally discovered as a dioxin-binding transcription factor involved in the metabolism of environmental toxicants and, in the past, we found it promotes aging phenotypes across species. Many AhR modulators may impact on aging and age-associated pathologies, but, whether their effects are actually AhR-dependent has never been explored. We show here for the first time that C. elegans AhR has protective effects against environmental insults such as UVB radiations and the xenobiotic BaP and identified a new critical role for AhR-bacterial diet interaction in animal lifespan, stress resistance, and age-associated pathologies.

physiology↗

bioRxiv2020

Lutein restores synaptic functionality in a C. elegans model for mitochondrial complex I deficiency

Complex I deficiency represents the most frequent pathogenetic cause of human mitochondriopathies. Therapeutic options for these neurodevelopmental life-threating disorders do not exist, partly due to the scarcity of appropriate model systems to study them. Caenorhabditis elegans is a genetically tractable model organism widely used to investigate neuronal pathologies. Here, we generated new C. elegans models for mitochondriopathies and showed that depletion of Complex I subunits recapitulates biochemical, cellular and neurodevelopmental aspects of the human diseases. Two models, nuo-5/NDUFS1- and lpd-5/NDUFS4-depleted animals, were exploited for a suppressor screening that identified lutein for its ability to rescue animals neurodevelopmental deficits. We uncovered overexpression of synaptic neuroligins as an evolutionarily conserved consequence of mitochondrial dysfunction, which we found to mediate an early cholinergic defect in C. elegans. We showed lutein exerts its beneficial effects by restoring neuroligin expression independently from its antioxidant activity, thus pointing to a possible novel pathogenetic target for the human disease.

neuroscience↗