Biology subjects

Marchi, N.

Publications and source records attributed to Marchi, N..

10 recordsLinked to original sources

bioRxiv2026

Environmentally relevant bisphenol mixtures modify heart-brain physiology, cerebrovascular structures, and transcriptomic profiles in zebrafish larvae

Environmental exposure involves pollutant mixtures. Building on evidence that individual bisphenols alter zebrafish larval physiology and transcriptomic profiles at ng/L concentrations, we assessed the effects of specific mixtures of BPS, BPF, and BPAF without (M1) or with (M2) BPA. Experimentally, M1 and M2 induced 4.16% and 6.54% mortality in zebrafish larvae, despite the concentration addition model predicting no toxicity. Both mixtures reduced swimming-locomotor activities. These behaviors were accompanied by organ-level functional defects, as in vivo optical mapping revealed bradycardia and increased high-frequency (30-80 Hz) brain oscillations for both mixtures, while M2 additionally altered low-frequency (0.2-4 Hz) brain activity. The neurophysiological changes were accompanied by neurovascular remodeling, with in vivo two-photon microscopy revealing decreased vascular length and branching. Finally, transcriptomic analysis revealed common M1- and M2-induced alterations linked to pathways of vascular function, neuronal communication, and metabolism. M2 altered additional pathways of cardiac and neuronal signaling, consistent with the reported organ-physiology effects. We discuss the environmental relevance of mixture exposures and assess whether BPA intensifies mixture-induced responses.

pharmacology and toxicology↗

bioRxiv2026

Long-lasting astrocyte remodeling in Dravet Syndrome Scn1a+/- mouse model.

BackgroundDravet syndrome (DS) is a prototypical developmental and epileptic encephalopathy caused by SCN1A gene mutations leading to NaV1.1 loss of function. The latter causes early-onset drug-resistant seizures and enduring cognitive and behavioral deficits. In this pathological context, the implication of astrocytes remains insufficiently explored. MethodsUsing a heterozygous Scn1a knock-out (Scn1a/-) mouse model that recapitulates the DS-human phenotype, we examine astrocyte remodeling at landmark disease stages, as defined by video-EEG and behavioral read-outs. ResultsFrom initial disease aggravation (PN20-35) to long-term stabilization (up to PN90), Scn1a/- mice showed increased hippocampal and cortical GFAP transcript and protein levels, compared to age-matched control littermates and to an earlier presymptomatic (<PN20) time point. During the aggravation phase in Scn1a/- mice, astrocyte branching, revealed by GFAP histological analysis and by intracellular delivery of Alexa Fluor 488 in hippocampal slices was increased but not sustained long-term. These disease-stage-dependent astrocyte modifications were not associated with macroscopic hippocampal sclerosis or cortical atrophy. To further study astrocyte remodeling during disease progression, we used biocytin diffusion following single-astrocyte loading to reveal an expanded astrocyte-astrocyte network in Scn1a/- mice long-term, along with increased Cx30 and Cx43 protein levels. An ethidium bromide uptake assay indicated impaired astrocytic hemichannel function in Scn1a/- mice long-term. Regionally, these long-term cellular and network astrocyte modifications coincided with augmented post-tetanic synaptic potentiation. DiscussionIn DS, astrocytes undergo a long-lasting network remodeling. We discuss how this astrocyte remodeling may be related to seizures as well as synaptic and cognitive deficits.

neuroscience↗

bioRxiv2025

A Microfluidic Platform for Whole-Membrane Integrity Profiling in Live Neuronal Cells

Structural and functional compromise of the cellular membrane are central mechanisms in the pathogenesis of numerous diseases, including neurodegenerative disorders such as Alzheimers and Parkinsons disease. However, existing techniques for assessing membrane integrity often lack the ability to provide dynamic, whole-cell measurements and are limited to localized damage detection or population-level analysis. There is a growing need for methods capable of monitoring membrane integrity over time at the single-cell level and across the entire membrane surface. In this study, we present a microfluidic platform for real-time, label-free assessment of membrane integrity by analyzing dielectric properties. We apply this system to investigate how different aggregated forms of -Synuclein (aSyn), a protein that plays a central role in the pathogenesis of Parkinsons disease and disrupts neuronal membranes. Our platform integrates electrokinetic microdevices with 3D microelectrodes and imaging, enabling continuous analysis of up to 30 live neuronal cells per hour under flow. By measuring electrorotation responses, we quantify changes in plasma membrane capacitance in response to monomeric, oligomeric, and fibrillar aSyn. This approach allows direct, time-resolved comparison of membrane-disruptive effects across different aSyn conformations with single-cell resolution and whole-membrane sensitivity.

bioengineering↗

bioRxiv2025

Astroglial deficiency for oligophrenin-1 contributes to intellectual disability

Neurodevelopmental disorders, including X-linked intellectual disability, autism spectrum disorder or schizophrenia, can result from the mutation of oligophrenin-1 (Ophn1), encoding a Rho-GTPase-activating protein. Ophn1 regulates synaptic development and function, in part via cytoskeleton reorganization, and is expressed in both neurons and astrocytes. Despite the crucial role of astrocytes in synapse function, altered in neurodevelopmental disorders, and their Ophn1 expression, the specific impact of astroglial Ophn1 deficiency on synaptic transmission and behavior remains unknown. Here, we show that Ophn1 deficiency postnatally in hippocampal astrocytes impairs synaptic transmission, short-term plasticity and spatial working memory in adults. This involves an adenosine A1 receptor-dependent presynaptic mechanism associated with astroglial morphological rearrangements resulting in increased astroglial synapse coverage. The structural, functional and behavioral alterations induced by astroglial Ophn1 deficiency are rescued in adults by pharmacological inhibition of the RhoA/ROCK pathway. Our findings uncover an important role for astroglial Ophn1 deficiency in synaptic and behavioral dysfunctions, pointing to a novel cellular therapeutic target for neurodevelopmental disorders.

neuroscience↗

bioRxiv2024

Sex-Specific Complement and Cytokine Imbalances in Drug-Resistant Epilepsy: Biomarkers of Immune Vulnerability

ObjectiveDrug-resistant epilepsy (DRE) poses significant challenges in treatment and management. While seizure-related alterations in peripheral immune players are increasingly recognized, the involvement of the complement system, central to immune function, remains insufficiently explored in DRE. This study aimed to investigate the levels of complement system components and their association with cytokine profiles in patients with DRE. MethodsWe analyzed serum samples from DRE patients (n = 46) and age- and sex-matched healthy controls (n = 45). Complement components and cytokines were quantified using Multi- and Single-plex ELISA. Statistical analyses examined relationships between complement molecules, cytokines, and clinical outcomes including epilepsy duration, Full-Scale Intelligence Quotient (FSIQ) scores, and age. ResultsWe found common alterations in all DRE cases, including significant complement deficiencies (C1q, Factor H, C4, C4b, C3, and C3b/iC3b) and detectable bFGF levels. DRE females showed significantly lower levels of TNF and IL-8 compared to healthy females. We observed a trend towards elevated CCL2 and CCL5 levels in DRE males compared to healthy males. These findings suggest potential sex dimorphism in immune profiles. Our analysis also indicated associations between specific complement and inflammatory markers (C2, IL-8, and IL-9) and Full-Scale Intelligence Quotient (FSIQ) scores in DRE patients. InterpretationOur study reveals sex-specific peripheral complement deficiencies and cytokine dysregulation in DRE patients, indicating an underlying immune system vulnerability. These findings provide new insights into DRE mechanisms, potentially guiding future research on complement and cytokine signaling toward personalized treatments for DRE patients.

neuroscience↗

bioRxiv2021

Genetic continuity of Indo-Iranian speakers since the Iron Age in southern Central Asia.

Since prehistoric times, South Central Asia has been at the crossroads of the movement of people, culture, and goods. Today, the Central Asias populations are divided into two cultural and linguistic groups: the Indo-Iranian and the Turko-Mongolian groups. Previous genetic studies unveiled that migrations from East Asia contributed to the spread of Turko-Mongolian populations in Central Asia and the partial replacement of the Indo-Iranian population. However, little is known about the origin of the latter. To shed light on this, we compare the genetic data on two current-day populations- Yaghnobis and Tajiks - with genome-wide data from published ancient individuals. The present Indo-Iranian populations from Central Asia display a strong genetic continuity with Iron Age samples from Turkmenistan and Tajikistan. We model Yaghnobis as a mixture of 93% Iron Age individual from Turkmenistan and 7% from Baikal. For the Tajiks, we observe a higher Baikal ancestry and an additional admixture event with a South Asian population. Our results, therefore, suggest that in addition to a complex history, Central Asia shows a remarkable genetic continuity since the Iron Age, with only limited gene flow.

genomics↗

bioRxiv2021

Codiversification of gut microbiota with humans

Some gut microbes have cospeciated with hominids, but whether they further codiversified with human populations is unclear. Here, we identify predominant gut microbial species sharing a parallel evolutionary history with human populations. Patterns of strain transfer between populations are generally consistent with an African origin, and suggest long-term vertical transmission over thousands of generations. We show the same strains also faithfully transmit between mothers and their children. Consistent with the development of intimate symbiosis, species with strongest patterns of codiversification have the smallest genomes. This study reveals long-term fidelity of gut microbiota with human populations through transmission among individuals living in close proximity. Dominance of specific strains in different populations is based in part on vertical transmission and they may provide population-specific health benefits. One-sentence summaryIdentification of gut microbes that codiversified with human populations.

evolutionary biology↗

bioRxiv2020

The mixed genetic origin of the first farmers of Europe

The precise genetic origins of the first Neolithic farming populations, as well as the processes and the timing of their differentiation, remain largely unknown. Based on demogenomic modeling of high-quality ancient genomes, we show that the early farmers of Anatolia and Europe emerged from a multiphase mixing of a Near Eastern population with a strongly bottlenecked Western hunter-gatherer population after the Last Glacial Maximum. Moreover, the population branch leading to the first farmers of Europe and Anatolia is characterized by a 2,500-year period of extreme genetic drift during its westward range expansion. Based on these findings, we derive a spatially explicit model of the population history of Southwest Asia and Europe during the late Pleistocene and early Holocene. One-Sentence SummaryEarly European farmers emerged from multiple post LGM mixtures and experienced extreme drift during their westward expansion.

evolutionary biology↗

bioRxiv2020

Robust and Gradient Thickness Porous Membranes for In Vitro Modeling of Physiological Barriers

Porous membranes are fundamental elements for tissue-chip barrier and co-culture models. However, the exaggerated thickness of commonly available membranes impedes an accurate in vitro reproduction of the biological multi-cellular continuum as it occurs in vivo. Existing techniques to fabricate membranes such as solvent cast, spin-coating, sputtering and PE-CVD result in uniform thickness films. To understand critical separation distances for various barrier and co-culture models, a gradient thickness membrane is needed. Here, we developed a robust method to generate ultrathin porous parylene C (UPP) membranes not just with precise thicknesses down to 300 nm, but with variable gradients in thicknesses, while at the same time having porosities up to 25%. We also show surface etching and increased roughness lead to improved cell attachment. Next, we examined the mechanical properties of UPP membranes with varying porosity and thickness and fit our data to previously published models, which can help determine practical upper limits of porosity and lower limits of thickness. Lastly, we validate a straightforward approach allowing the successful integration of the UPP membranes into a prototyped 3D-printed scaffold enabling in vitro barrier modeling and investigation of cell-cell interplay over variable distances using thickness gradients.

bioengineering↗

bioRxiv2019

The mGlu7 receptor provides protective effects against epileptogenesis and epileptic seizures

Finding new targets to control or reduce seizure activity is essential to improve the management of epileptic patients. We hypothesized that activation of the pre-synaptic and inhibitory metabotropic glutamate receptor type 7 (mGlu7) reduces spontaneous seizures. We tested LSP2-9166, a recently developed mGlu7/4 agonist with unprecedented potency on mGlu7 receptors, in two paradigms of epileptogenesis. In a model of chemically induced epileptogenesis (pentylenetetrazol systemic injection), LSP2-9166 induces an antiepileptogenic effect rarely observed in preclinical studies. In particular, we found a bidirectional modulation of seizure progression by mGlu4 and mGlu7 receptors, the latter preventing kindling. In the intra-hippocampal injection of kainic acid mouse model that mimics the human mesial temporal lobe epilepsy, we found LSP2-9166 reduced seizure frequency and hippocampal sclerosis. LSP2-9166 also acts as an anti epileptic drug on established seizures in both models tested. Specific modulation of the mGlu7 receptor could represent a novel approach to reduce pathological network remodeling.

neuroscience↗