Biology subjects

Devisscher, L.

Publications and source records attributed to Devisscher, L..

8 recordsLinked to original sources

bioRxiv2026

Characterising sleep spindle emergence in infancy: Effects of prematurity and early locomotor intervention

Study objectives: Sleep spindles are thalamocortical oscillations evolving during early brain maturation. In adults, they support memory consolidation and are organised into rhythmic "trains" thought to support memory reactivation. How this temporal organisation emerges in infancy, and whether prematurity or early sensorimotor experience shapes it, remains unclear. This study characterised infant spindles and investigated how prematurity and early locomotor training affect their temporal and spatial organisation, providing insight into early brain maturation. Methods: Daytime high-density EEG sleep recordings were analysed in 50 infants born full-term (n=12) or very preterm (n=38, including 12 who received locomotor training) at 2 months corrected age. Spindle temporal organisation was analysed using a two-step Morlet wavelet transform to quantify slow modulations of spindle-band power (11-16Hz). Time-frequency decomposition around spindle onset was used to identify significant spindle-band scalp-wide activity, and topographical maps were statistically compared between groups. Results: All groups showed rhythmic spindle organisation, three times slower than in adults, with no group differences. Untrained preterm infants showed a more diffuse spindle-band activity than the distinct frontal and central clusters observed in full-term infants. Trained preterm infants exhibited a spatial distribution closely resembling that of full-term infants, although their frontal spindle density was lower than in both other groups. Conclusions: Spindle rhythmic organisation emerged early in infancy and remained unaffected by prematurity or locomotor training. Prematurity was associated with more diffuse spindle-band activity, suggesting reduced cortical specialisation, whereas trained preterm infants showed a spatial distribution resembling that of full-term infants, suggesting that early locomotor experience may influence thalamocortical organisation.

neuroscience↗

bioRxiv2026

Pharmacological inhibition of deubiquitinase UCH-L1 by LDN57444 sensitises hepatocellular carcinoma to sorafenib by reverting drug-induced adaptive responses

Background and aimsTherapeutic outcomes for advanced hepatocellular carcinoma remain inadequate, despite recent advances using immunotherapy. Long-term effectiveness of systemic therapies, including second-line multi-tyrosine kinase inhibitor sorafenib, is limited by resistance mechanisms and adverse effects. Upregulated deubiquitinase UCH-L1 is frequently correlated with poor prognosis in cancers. Here, we investigated the therapeutic potential of combining pharmacological UCH-L1-inhibition with sorafenib in HCC. MethodsUCH-L1 expression was analysed in TCGA-LIHC data and patient-derived HCC tissues. Sorafenib and LDN57444 effects were evaluated in vitro in cytotoxicity and invasion assays. Gene and protein expression were examined by RT-qPCR, Western blotting and immunohistochemistry. In vivo efficacy of drug synergy was assessed in an orthotopic xenograft mouse HCC model. ResultsIn silico data-analysis revealed significantly higher UCH-L1 levels in patient HCC tumours versus non-tumour, associated with reduced overall survival. Low-dose sorafenib upregulated UCH-L1 in HCC cell line Hep3B. Paradoxically, this also promoted invasiveness and sustained MEK1/2-ERK1/2-pathway activation. Combining low-dose sorafenib with LDN57444 produced strong synergistic cytotoxicity in vitro, reverted MAPK-activation and suppressed invasion. Consistently, at low sorafenib dose co-treatment with LDN57444 completely inhibited tumour growth of Hep3B xenografts and enhanced sorafenib efficacy. ConclusionLDN57444 sensitises HCC cells to low-dose sorafenib by reverting drug-induced pro-oncogenic signalling and thereby strongly synergises with sorafenib to enhance anti-tumour efficacy in a HCC mouse model. This presents UCH-L1 as a player in treatment-induced adaptive response and supports further exploring UCH-L1-targeting in combination with sorafenib as therapeutic avenue for advanced HCC. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/725527v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@176dc91org.highwire.dtl.DTLVardef@8acae8org.highwire.dtl.DTLVardef@f71bborg.highwire.dtl.DTLVardef@1f3c5aa_HPS_FORMAT_FIGEXP M_FIG C_FIG Lay summaryThis study explores a new treatment approach for hepatocellular carcinoma (HCC) by combining two drugs: LDN57444, which blocks the enzyme UCH-L1, and sorafenib, a FDA-approved multi-tyrosine kinase inhibitor. We evaluated the effect of this drug combination in vitro using a HCC cell line and in an mouse HCC-model. The drug combination displayed strong, synergy in lowering HCC cell viability, and greatly reduced invasiveness and in vivo tumour growth. LDN57444 sensitised HCC cells to low doses of sorafenib by preventing UCH-L1-mediated activation of pro-oncogenic signalling. These findings highlight the potential of this new drug combination for treating advanced HCC thereby potentially reducing side-effects and countering drug resistance. Impact and implicationsOur preclinical research introduces a novel combination strategy against advanced HCC that holds potential to improve existing therapies, particularly the second-line multi-tyrosine kinase inhibitor sorafenib. The proposed combination of sorafenib with an inhibitor of the deubiquitinase UCH-L1 not only enhances sorafenib efficacy but present promise to also counter resistance mechanisms. Moreover, because effective responses are achieved at lower drug doses, this may in addition reduce therapy-associated adverse effects further increasing potential impact. While sorafenib is FDA-approved, the UCH-L1 inhibitor LDN57444 needs further (clinical) development to bring our promising findings to full translational potential for HCC patients and physicians.

cancer biology↗

bioRxiv2025

Characterization of aperiodic and theta activity in preterm infants using EEG: Insights into cerebral maturation and inter-individual variability

Disrupting critical processes of brain development, preterm birth interferes with the maturation of brain networks and functional activity, including theta oscillations that are thought to play a key role in early network formation. Traditional EEG spectral analyses have indicated marked development of theta power in early infancy, but these approaches mix oscillatory and non-oscillatory activity, limiting insights into the mechanisms underlying the neural changes. Using spectral parameterization, we aimed to evaluate developmental changes in aperiodic activity and periodic theta power in infants born very preterm compared to full-terms, and to further explore whether clinical factors and brain microstructure could explain the inter-individual variability within preterms. High-density EEG was acquired during active/REM sleep at term-equivalent age (TEA) and 2 months corrected age (2mCA) in 41 very preterm infants (born <32 weeks gestational age [GA]; mean {+/-} standard deviation: 26.9{+/-}1.7 weeks) and 13 full-term controls (born [≥]37 weeks GA; 40.1{+/-}1 weeks). Spectral parameterization was used to extract aperiodic components (offset, exponent) and periodic theta power globally and across spatial clusters of electrodes (anterior, central, posterior). From TEA to 2mCA, offset, exponent, and theta power increased with no differences between preterm and full-term infants. At TEA, metrics of aperiodic activity were stronger in anterior compared with posterior areas, but this regional landscape shifted by 2mCA with pronounced increases in aperiodic offset and exponent in posterior areas from TEA to 2mCA. Within preterms, inter-individual variability in aperiodic and periodic activity at TEA was partly explained by clinical risk factors: male sex, lower gestational-age at birth, small weight at birth, and invasive ventilation were linked to alterations of aperiodic offset, exponent and theta power. Additionally, higher theta power at TEA correlated with lower cortical fractional anisotropy assessed with diffusion MRI at the same age, consistently with more advanced maturation of the brain. Collectively, these findings indicate that EEG spectral parameterization combined with spatial analysis provides a sensitive framework for characterizing the postnatal maturation of brain activity in infants, as well as early vulnerabilities associated with prematurity and perinatal adversity.

neuroscience↗

bioRxiv2025

Differential microstructural development within sensorimotor cortical regions: A diffusion MRI study in preterm and full-term infants

The sensorimotor system develops early in utero and supports the emergence of body representations critical for perception, action, and interaction with environment. While somatotopic protomaps are already developed in the primary somatosensory and motor cortices in late pregnancy, little is known about the anatomical substrates of this functional specialization. In this study, we aimed to decipher the microstructural properties of these regions in the developing brain. Using advanced diffusion MRI and post-processing tools, we parcellated the pre- and post-central gyri into microstructurally distinct clusters along the lateral-to-medial axis in full-term neonates, confirming the early differentiation within sensorimotor regions. These clusters were further analyzed in preterm infants scanned near birth and at term-equivalent age (TEA), compared with another group of full-term neonates. Applying a multivariate Mahalanobis distance approach, we quantified deviations in preterm cortical microstructure relative to the full-term reference. Preterm infants showed significant region- and position-specific deviations at both ages, though these were smaller at TEA, consistently with ongoing maturation during the pre-term period. Differences between the pre- and post-central gyri, and along the somatotopic axis, suggested differential vulnerability to prematurity. In particular, the motor regions appeared to be at a more advanced stage of maturation close to birth and less vulnerable at TEA than somatosensory regions. An opposite trend was observed for lateral positions related to mouth representation compared with intermediary and medial positions. These findings support the notion that early sensorimotor cortical specialization is microstructurally emergent during gestation and sensitive to atypical developmental context of preterm birth.

neuroscience↗

bioRxiv2024

PPARalpha-ERRalpha crosstalk mitigates metabolic dysfunction-associated steatotic liver disease progression

Background and aimsMetabolic dysfunction-associated steatotic liver disease (MASLD) is now the most common liver disease worldwide. This study investigates how targeting two key nuclear receptors involved in hepatic energy metabolism, peroxisome proliferator-activated receptor alpha (PPAR) and estrogen-related receptor alpha (ERR), impacts MASLD. MethodsThe PPAR agonist pemafibrate and/or ERR inverse agonist C29 were administered in a short- and long-term Western diet plus fructose model, and a diabetic-background streptozotocin-Western diet model (STZ-WD). Liver morphology, histological samples, serum metabolites, RNA and protein levels were analysed and scanning electron microscopy was performed. In addition, we performed cell-based assays and immunohistochemistry and immunofluorescence stainings with light and super-resolution confocal microscopy of healthy, MASLD and MASH human livers. ResultsThe ligand combinations efficacy was underscored by reduced liver steatosis in all the mouse models. Both long-term models showed improvements in body weight and liver morphology, alongside reductions in inflammation and fibrosis. Additionally, tumor formation was prevented in the STZ-WD mice model. Cell-based assays demonstrated that ERR inhibits PPARs activity, likely explaining why ERR blockage improves inflammatory and lipid metabolism gene profiles and enhances lipid-lowering effects. Complementary RNA sequencing and shotgun proteomics, combined with enrichment analysis, jointly identified downregulated serum amyloid A1/A2 as an essential component underlying the combination treatments effectiveness. MASLD/MASH patient livers showed reduced PPAR and increased ERR levels supporting disrupted NR crosstalk in the hepatocyte nucleus. ConclusionOur study comprehensively supports that dual nuclear receptor targeting by simultaneously increasing PPAR and diminishing ERR activity may represent a viable novel strategy against MASLD. Lay summaryOur study using three distinct MASLD mouse models shows that a simultaneous targeting of PPAR and ERR reduces liver fat, fibrosis, inflammation, and tumor formation. The combination treatment modifies lipid metabolism pathways, and uniquely lowers levels of serum amyloid A1/A2 in the liver. Impact and implicationsOur research introduces a novel therapeutic strategy against MASLD by simultaneously increasing PPAR activity while diminishing ERR activity. With PPAR agonists already tested in phase III clinical trials, ERR ligands/modulators need further (clinical) development to make our findings applicable to both MASLD patients and physicians.

pharmacology and toxicology↗

bioRxiv2024

Temporal dynamics and maturation of resting-state activity in preterm infants

By interfering with the normal sequence of mechanisms serving the brain maturation, premature birth and related stress can alter perinatal experiences, with potential long-term consequences on a childs neurodevelopment. The early characterization of brain functioning and maturational changes is thus of critical interest in premature infants who are at high risk of atypical outcomes and could benefit from early diagnosis and dedicated interventions. Using high-density electroencephalography (HD-EEG), we recorded brain activity in extreme and very preterm infants at the equivalent age of pregnancy term (n=43), and longitudinally 2-months later (n=33), compared with full-term born infants (n=14). We characterized the maturation of brain activity by using a dedicated microstate analysis to quantify the spatio-temporal dynamics of the spontaneous transient network activity while controlling for vigilance states. The comparison of premature and full-term infants first showed slower dynamics as well as altered spatio-temporal properties of brain activity in preterm infants. Maturation of functional networks between term-equivalent age and 2 months later in preterms was linked to the emergence of faster dynamics, manifested in part by shorter duration of microstates, as well as an evolution in the spatial organization of the dominant microstates. The inter-individual differences in the temporal dynamics of brain activity at term-equivalent age were further impacted by sex (with slower microstate dynamics in boys) and by gestational age at birth for some microstate dynamics but not by other considered risk factors. This study highlights the potential of the microstate approach to reveal maturational properties of the emerging brain network activity in premature infants.

neuroscience↗

bioRxiv2021

Spatial proteogenomics reveals distinct and evolutionarily-conserved hepatic macrophage niches

The liver is the largest solid organ in the body, yet it remains incompletely characterized. Here, we present a spatial proteogenomic atlas of the healthy human and murine liver combining single-cell CITE-seq, single-nuclei sequencing, spatial transcriptomics and spatial proteomics. By integrating these multi-omic datasets, we provide validated strategies to reliably discriminate and localize all hepatic cells. We then align this atlas across seven species, revealing the conserved program of bona fide Kupffer cells and bile-duct macrophages. We also uncover the respective spatially-resolved cellular niches of these macrophages and the microenvironmental circuits driving their unique transcriptomic identities. We demonstrate that bile-duct macrophages are induced by local lipid exposure, while Kupffer cells crucially depend on their crosstalk with hepatic stellate cells via the evolutionarily-conserved ALK1-BMP9/10 axis.

immunology↗

bioRxiv2020

Human hepatocyte PNPLA3 148M exacerbates rapid non-alcoholic steatohepatitis development in chimeric mice

Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in patatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepatocytes with PNPLA3 148I and 148M variants engrafted in the livers of chimeric mice respond to a hypercaloric Western-style diet. As early as 4 weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatohepatitis selectively in the human graft, followed by pericellular fibrosis after 8 weeks of hypercaloric feeding. The PNPLA3 148M variant, either from a homozygous 148M human donor or overexpressed in a homozygous 148I donor background, caused widespread microvesicular steatosis and even more severe steatohepatitis. We conclude that PNPLA3 148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetic variants associated with advanced fatty liver diseases.

pathology↗