Biology subjects

Berger, P.

Publications and source records attributed to Berger, P..

16 recordsLinked to original sources

bioRxiv2026

A distinct signature of interferon-stimulated genes linked to cross-protection against secondary viral infections in primary bronchial epithelial cells

Respiratory viral infections, such as those caused by rhinovirus, adenovirus, influenza, respiratory syncytial virus (RSV), and SARS-CoV-2, represent a major global health challenge. Despite extensive research, effective and specific antiviral treatments for these infections are still lacking, with patient care often limited to symptomatic relief. The SARS-CoV-2 pandemic, alongside the emergence of avian flu H1N1 and Nipah virus, has underscored the critical role of the respiratory tract as a critical viral target. Respiratory viral infections exhibit marked variability in infectivity and disease severity across different age groups. Epidemiological and cell-based evidence highlights distinct impacts on pediatric and adult populations. For instance, the COVID-19 disproportionately affected the elderly, while viruses like rhinovirus and adenovirus often cause severe morbidity in children. Additionally, clinical studies indicate that a primary respiratory infection can provide transient protection against subsequent infections by the same or different respiratory viruses. In this study, we utilized a differentiated bronchial epithelial (BE) model derived from pediatric and adult donors to assess age-dependent differences under resting conditions and during viral infections. We investigated how donor age influences infection susceptibility and viral spread within the BE, focusing on the transcriptional response to rhinovirus types A and C, and adenovirus type 5. Importantly, we demonstrate that prior viral infection confers protection against subsequent infections, regardless of donor age or the initial virus type. This cross-protection is driven by interferon signaling, leading to the expression of a narrow and specific set of interferon-stimulated genes (ISGs) in both infected and bystander cells. Notably, IFI44L shows the strongest correlation with the level of cross protection and that its overexpression alone significantly reduces viral infection of BE. These findings suggest a distinctive, interferon-driven innate immune response profile in the BE, offering critical insights for the development of new therapeutic strategies against respiratory viral infections.

microbiology↗

bioRxiv2025

Grammar acquisition in preschool children is related to white matter maturation of the dorsal language network

In preschool years, children take important steps in grammar acquisition, which are essential to learning their native language. A central aspect is the acquisition of the morpho-syntactic rule system, which forms an intersection between words and sentences. In adults, rule-based linguistic processes are supported by the dorsal fiber pathway to BA44, the arcuate fascicle. This pathway matures relatively late in development, raising the question of whether it already supports grammar processes in the early preschool years, or whether early grammar acquisition is supported by different, earlier-maturing fiber pathways. In two independent samples of 3- to 5-year-old children (N = 90 and N = 30), we examined the association between the maturation of fiber pathways of the language network and childrens noun plural assignment as an index of their morpho-syntactic abilities. This revealed consistent differences between 3-year-olds and 4- to 5-year-olds. The 4- and 5-year-olds, but not 3-year-olds, showed a relation of morpho-syntax with both the dorsal pathway to BA44, supporting syntactic processes, and the dorsal pathway to BA6, supporting phonological processes in adults. Our results suggest that, in contrast to adults, preschool-aged children rely on both dorsal fiber pathways for morpho-syntax. This difference might point to different processing strategies reflecting the transition from phonology-based statistical learning to rule-based learning in grammar acquisition.

developmental biology↗

bioRxiv2025

A Sacrificial 3D Printed Vessel-on-Chip Demonstrates a Versatile Approach to Model Connective Tissue Pathology

For in vitro organ models, perfused vasculature is crucial to overcome nutrient diffusion limits and to generate immunocompetent models by allowing trans-endothelial migration of immune cells in and out of the tissue. However, vasculature is often disregarded due to its complexity to generate and the necessity to integrate flow. The aim here was to overcome these limitations by combining 3D printing and multi-organ-chip technology to generate a vascularized, fibroblast-populated connective tissue matrix on-chip. A 3D printed, sacrificial, water-dissolvable structure was incorporated into a multi-organ-chip to generate hollow channels within a collagen/fibrin hydrogel. Subsequently, the channels were populated with endothelial cells. Different hydrogel concentrations of fibrin were used to mimic healthy and early granulation tissue. The vessels were perfused, and stable metabolic/viability conditions (lactate dehydrogenase, glucose, lactate) acquired after 3 days for 7 days total. In high fibrin gels, angiogenic sprouting and increased secretion of angiogenic cytokines was observed. Perfusion with monocytes revealed differentiation into macrophages and migration across the endothelium into the tissue. In conclusion, the versatile, easy method to pattern hydrogels in multi-organ-chips can serve as the basis to build the next generation of vascularized, immunocompetent human organ models, and opens new possibilities to study health and disease.

bioengineering↗

bioRxiv2024

Primary Human Neutrophils and Monocytes/Macrophages Migrate along Endothelial Cell Boundaries to Optimize Search Efficiency

Neutrophils and monocytes/macrophages are sentinels of inflammatory signals. To reach the sites of action, both cell types attach to and then transmigrate the endothelial cell layer that lines the luminal side of blood vessels. While it has been reported that neutrophils and monocytes/macrophages actively migrate along the surface of the vasculature, it remains elusive if and how these motion pattern augment the efficiency of the immune system. Here, we conducted co-culture experiments of primary human monocytes and neutrophils, respectively, with human umbilical vein endothelial cells (HUVECs). Combining classical biomedical approaches with quantitative image analysis and numerical models, we find that immune cells simultaneously increase the number of sampled cells vs. traveled distance and sensitivity to chemokines by migrating along endothelial cell-cell boundaries. Collectively, these findings establish search optimization of neutrophils and monocytes/macrophages through limitation of motion pattern to cell-cell boundaries.

cell biology↗

bioRxiv2024

Modeling the connectome of joint attention in infancy predicts Theory of Mind in preschool-age

Our ability to reason about other peoples mental states, labeled Theory of Mind (ToM), is critical for successful human interaction. Despite its importance for human cognition, early predictors of individual ToM development are lacking. Here, we trained a computational model to identify whole-brain connectivity patterns predictive of joint attention, from resting-state fMRI data of 8-15-month-old infants, and tested whether the identified connectome would also predict ToM capacity later in development. First, the model significantly predicted joint attention scores in an independent infant sample. Crucially, the identified connectome did indeed predict ToM in children aged 2-5 years. The default network and its interaction with the ventral attention network formed dominant connections of the network, suggesting that the interplay of bottom-up attention and higher-order cognition paves the way for mature social cognition. These findings provide an early marker for individual differences in social cognitive development, with high potential for the early diagnosis of social cognitive disorders.

neuroscience↗

bioRxiv2024

A dorsal versus ventral network for understanding others in the developing brain

Young children strongly depend on others, and learning to understand their mental states (referred to as Theory of Mind, ToM) is a key challenge of early cognitive development. Traditionally, ToM is thought to emerge around the age of 4 years. Yet, in non-verbal tasks, preverbal infants already seem to consider others mental states when predicting their actions. These early non-verbal capacities, however, seem fragile and distinct from later-developing verbal ToM. So far, little is known about the nature of these early capacities and the neural networks supporting them. To identify these networks, we investigated the maturation of nerve fiber connections associated with childrens correct non-verbal action prediction and compared them with connections supporting verbal ToM reasoning in 3- to 4-year-old children, that is, before and after their breakthrough in verbal ToM. This revealed a ventral network for non-verbal action prediction versus a dorsal network for verbal ToM. Non-verbal capacities were associated with maturational indices in ventral fiber tracts connecting regions of the salience network, involved in bottom-up social attention processes. In contrast, verbal ToM performance correlated with maturational indices of the arcuate fascicle and cingulum, which dorsally connect regions of the default network, involved in higher-order social cognitive processes including ToM in adults. As non-verbal tasks were linked to connections of the salience network, young children may make use of salient perceptual social cues to predict others actions, questioning theories of mature ToM before 4 years. SignificanceAs highly social beings, humans frequently reason about other peoples thoughts, termed Theory of Mind (ToM). While ToM is traditionally assumed not to emerge before 4 years, preverbal infants already seem to consider others thoughts when predicting their actions non-verbally. This raises the question of when ToM develops and what explains this discrepancy. We show that young childrens success in non-verbal tasks is related to different neural networks than those involved in mature verbal ToM. While verbal ToM was linked to ToM network connections, younger childrens non-verbal capacities were associated with the maturation of connections of the salience network. This indicates that, instead of mature ToM, young children might utilize salient social cues to predict others actions.

neuroscience↗

bioRxiv2023

A novel in vitro tubular model to recapitulate features of distal airways: the bronchioid

BackgroundAirflow limitation is the hallmark of obstructive pulmonary diseases, with the distal airways representing a major site of obstruction. Although numerous in vitro models of bronchi already exist, there is currently no culture system for obstructive diseases that reproduces the architecture and function of small airways. Here, we aimed to engineer a model of distal airways to overcome the limitations of current culture systems. MethodsWe developed a so-called bronchioid model by encapsulating human bronchial adult stem cells derived from clinical samples in a tubular scaffold made of alginate gel. ResultsThis template drives the spontaneous self-organization of epithelial cells into a tubular structure. Fine control of the level of contraction is required to establish a model of the bronchiole, which has a physiologically relevant shape and size. 3D imaging, gene expression and single-cell RNA-seq analysis of bronchioids made of bronchial epithelial cells revealed tubular organization, epithelial junction formation and differentiation into ciliated and goblet cells. Ciliary beating is observed, at a decreased frequency in bronchioids made of cells from COPD patients. The bronchioid can be infected by rhinovirus. An air-liquid interface is introduced that modulates gene expression. ConclusionHere, we provide a proof of concept of a perfusable bronchioid with proper mucociliary and contractile functions. The key advantages of our approach, such as the air-liquid interface, lumen accessibility, recapitulation of pathological features and possible assessment of clinically relevant endpoints, will make our pulmonary organoid-like model a powerful tool for preclinical studies.

physiology↗

bioRxiv2023

CXCR4 blockade alleviates pulmonary and cardiac outcomes in early COPD

Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disease lacking effective treatment. Focusing on early COPD should help to discover disease modifying therapies. We aimed to examine the role of the CXCL12/CXCR4 axis in early COPD from both human samples and murine models. Blood samples and lung tissues of early COPD patients and controls were obtained in order to analyse CXCL12 and CXCR4 levels. To generate an early COPD model, ten-week-old male C57BL/6J mice were exposed to cigarette smoke (CS) for 10 weeks and intranasal instillations of polyinosinic-polycytidylic acid (poly(I:C)) for the last 5 weeks to mimic exacerbations. CXCR4 expressing cells number was increased in the blood of patients with COPD, as well as in the blood of exposed mice. Lung CXCL12 expression was higher in both early COPD patients and exposed mice. Exposed mice presented mild airway obstruction, peri-bronchial fibrosis and right heart thickening. The density of fibrocytes expressing CXCR4 was increased in the bronchial submucosa of these mice. Conditional inactivation of CXCR4 at adult stage as well as pharmacological inhibition of CXCR4 with plerixafor injections improved lung function, reduced inflammation, and protected against CS and poly-(I:C)-induced airway and cardiac remodeling. CXCR4-/- and plerixafor-treated mice also had less CXCR4-expressing circulating cells and a lower density of peri-bronchial fibrocytes. We demonstrate that targeting CXCR4 has beneficial effects in an animal model of early COPD and provide a framework to translate these preclinical findings to clinical settings in a drug repurposing approach. Clinical relevanceWe demonstrate that CXCL12/CXCR4 axis plays an important role in the pathogenesis of early COPD. Inhibition of this axis improves lung function and cardiac tissue remodeling, supporting the future use of CXCR4 inhibitors to slow down the progression of the disease.

pathology↗

bioRxiv2022

Short-range interactions between fibrocytes and CD8+ T cells in COPD bronchial inflammatory response

AbstractBronchi of chronic obstructive pulmonary disease (COPD) are the site of extensive cell infiltration, allowing persistent contacts between resident cells and immune cells. Tissue fibrocytes interaction with CD8+ T cells and its consequences were investigated using a combination of in situ, in vitro experiments and mathematical modeling. We show that fibrocytes and CD8+ T cells are found in vicinity in distal airways and that potential interactions are more frequent in tissues from COPD patients compared to those of control subjects. Increased proximity and clusterization between CD8+ T cells and fibrocytes are associated with altered lung function. Tissular CD8+ T cells from COPD patients promote fibrocyte chemotaxis via the CXCL8-CXCR1/2 axis. Live imaging shows that CD8+ T cells establish short-term interactions with fibrocytes, that trigger CD8+ T cell proliferation in a CD54- and CD86-dependent manner, pro-inflammatory cytokines production, CD8+ T cell cytotoxic activity against bronchial epithelial cells and fibrocyte immunomodulatory properties. We defined a computational model describing these intercellular interactions and calibrated the parameters based on our experimental measurements. We show the models ability to reproduce histological ex vivo characteristics, and observe an important contribution of fibrocyte-mediated CD8+ T cell proliferation in COPD development. Using the model to test therapeutic scenarios, we predict a recovery time of several years, and the failure of targeting chemotaxis or interacting processes. Altogether, our study reveals that local interactions between fibrocytes and CD8+ T cells could jeopardize the balance between protective immunity and chronic inflammation in bronchi of COPD patients.

pathology↗

bioRxiv2022

Children's syntax is supported by the maturation of BA44 at 4 years, but of the posterior STS at 3 years of age

Within the first years of life, children learn major aspects of their native language. However, the ability to process complex sentence structures, a core faculty in human language called syntax, has been found to emerge only slowly. A milestone in the acquisition of syntax is reached around the age of 4, when children learn a variety of syntactic concepts, including, for example, subordinate clauses. Here, we ask which maturational changes in the childs brain underlie the emergence of syntactic abilities around this critical age. We relate markers of cortical brain maturation to 3- and 4-year-olds syntactic in contrast to other language abilities. Our results show that distinct cortical brain areas support syntax in the two age groups: While 3-year-old childrens syntactic abilities were associated with increased surface area in the most posterior part of the left superior temporal sulcus, 4-year-old children showed an association with cortical thickness in the left posterior part of Brocas area, i.e. BA44. The present findings suggest that syntactic abilities rely on the maturation of distinct cortical regions in 3- compared to 4-year-olds. The observed shift to more mature regions involved in syntax may underlie the behavioral milestones in syntax acquisition around 4 years of age.

neuroscience↗

bioRxiv2021

Maturation of distinct neural components of the cognitive control network support early development of inhibitory control

Goal-directed behavior crucially relies on our capacity to suppress impulses and predominant behavioral responses. This ability, called inhibitory control, emerges in early childhood with marked improvements between 3 and 4 years. Here, we ask which brain structures are related to the emergence of this critical ability. Using a multimodal approach, we relate the pronounced behavioral improvements in different facets of 3-and 4-year-olds (N = 37, 20 female) inhibitory control to structural indices of maturation in the developing brain assessed with MRI. Our results show that cortical and subcortical structure of core regions in the adult cognitive control network, including the PFC, thalamus, and the inferior parietal cortices, are associated with early inhibitory functioning in preschool children. Probabilistic tractography revealed an association of frontoparietal (i.e., the superior longitudinal fascicle) and thalamocortical connections with early inhibitory control. Notably, these associations to brain structure were distinct for different facets of early inhibitory control, often referred to as motivational ( hot) and cognitive ( cold) inhibitory control. Our findings thus reveal the structural brain networks and connectivity related to the emergence of this core faculty of human cognition. Significance StatementThe capacity to suppress impulses and behavioral responses is crucial for goal-directed behavior. This ability, called inhibitory control, develops between the ages of 3 and 4 years. The factors behind this developmental milestone have been debated intensely for decades, however, the brain structure that underlies the emergence of inhibitory control in early childhood is largely unknown. Here, we relate the pronounced behavioral improvements in inhibitory control between 3 and 4 years with structural brain markers of grey matter and white matter maturation. Using a multimodal approach that combines analyses of cortical surface structure, subcortical structures, and white matter connectivity, our results reveal the structural brain networks and connectivity related to this core faculty of human cognition.

neuroscience↗

bioRxiv2021

SARS-CoV-2 transmission via apical syncytia release from primary bronchial epithelia and infectivity restriction in children epithelia

The beta-coronavirus SARS-CoV-2 is at the origin of a persistent worldwide pandemic. SARS-CoV-2 infections initiate in the bronchi of the upper respiratory tract and are able to disseminate to the lower respiratory tract eventually causing acute severe respiratory syndrome with a high degree of mortality in the elderly. Here we use reconstituted primary bronchial epithelia from adult and children donors to follow the infection dynamic following infection with SARS-CoV-2. We show that in bronchial epithelia derived from adult donors, infections initiate in multi-ciliated cells. Then, infection rapidly spread within 24-48h throughout the whole epithelia. Within 3-4 days, large apical syncytia form between multi-ciliated cells and basal cells, which dissipate into the apical lumen. We show that these syncytia are a significant source of the released infectious dose. In stark contrast to these findings, bronchial epithelia reconstituted from children donors are intrinsically more resistant to virus infection and show active restriction of virus spread. This restriction is paired with accelerated release of IFN compared to adult donors. Taken together our findings reveal apical syncytia formation as an underappreciated source of infectious virus for either local dissemination or release into the environment. Furthermore, we provide direct evidence that children bronchial epithelia are more resistant to infection with SARS-CoV-2 providing experimental support for epidemiological observations that SARS-CoV-2 cases fatality is linked to age. Significance StatementBronchial epithelia are the primary target for SARS-CoV-2 infections. Our work uses reconstituted bronchial epithelia from adults and children. We show that infection of adult epithelia with SARS-CoV-2 is rapid and results in the synchronized release of large clusters of infected cells and syncytia into the apical lumen contributing to the released infectious virus dose. Infection of children derived bronchial epithelia revealed an intrinsic resistance to infection and virus spread, probably as a result of a faster onset of interferon secretion. Thus, our data provide direct evidence for the epidemiological observation that children are less susceptible to SARS-CoV-2.

microbiology↗

bioRxiv2020

Antagonism Between Brain Regions Relevant for Cognitive Control and Emotional Memory Facilitates the Generation of Humorous Ideas

The ability to generate humor gives rise to positive emotions and thus facilitate the successful resolution of adversity. Although there is consensus that inhibitory processes might be related to broaden the way of thinking, the neural underpinnings of these mechanisms are largely unknown. Here, we use functional Magnetic Resonance Imaging, a humorous alternative uses task and a stroop task, to investigate the brain mechanisms underlying the emergence of humorous ideas in 24 subjects. Neuroimaging results indicate that greater cognitive control abilities are associated with increased activation in the amygdala, the hippocampus and the superior and medial frontal gyrus during the generation of humorous ideas. Examining the neural mechanisms more closely shows that the downregulation of frontal brain regions is associated with an upregulation in the amygdala, which is concurrently linked with an increased number of humorous ideas and enhanced amygdala responses during the task. Our data therefore suggests that a neural antagonism previously related to the emergence and regulation of negative affective responses, is linked with the generation of emotionally positive ideas and may represent an important neural pathway supporting mental health.

neuroscience↗

bioRxiv2020

Characterizing the Theory of Mind Network in Schizophrenia Reveals a Sparser Network Structure

Impaired social functioning is a hallmark of schizophrenia and altered functional integration between distant brain regions are expected to account for signs and symptoms of the disorder. The functional neuroarchitecture of a network relevant for social functioning, the mentalizing network, is however poorly understood. In this study we examined dysfunctions of the mentalizing network in patients with schizophrenia compared to healthy controls via dynamic causal modelling and an interactive social decision-making game. Network characteristics were analyzed on a single subject basis whereas graph theoretic metrics such as in-degree, out-degree and edge-connectivity per network node were compared between the groups. The results point to a sparser network structure in patients with schizophrenia and highlight the dorsomedial prefrontal cortex as a disconnected network hub receiving significantly less input from other brain regions in the network. Further analyses suggest that integrating pathways from the right and the left temporo-parietal junction into the dorsomedial prefrontal cortex were less frequently found in patients with schizophrenia. Brain and behavior analyses further suggest that the connectivity-intactness within the entire network is associated with functional interpersonal behavior during the task. Thus, the neurobiological alterations within the mentalizing network in patients with schizophrenia point to a specific integration deficit between core brain regions underlying the generation of higher-order representations and thereby provide a potential treatment target.

neuroscience↗

bioRxiv2020

Paladin is a PI(4,5)P2 phosphoinositide phosphatase that regulates endosomal signaling and angiogenesis

Cell signaling governs cellular behavior and is therefore subject to tight spatiotemporal regulation. Signaling output is regulated by specialized cell membranes and vesicles which contain unique combinations of lipids and proteins. The phospholipid phosphatidylinositol 4,5-bisphosphate, (PI(4,5)P2), an important component of the plasma membrane as well as other subcellular membranes, is involved in multiple processes, including signaling. However, which enzymes drive the formation and degradation of non-plasma membrane PI(4,5)P2, and their impact on cell signaling and function at the organismal level are unknown. Here we show in a mouse model that Paladin is a vascular PI(4,5)P2 phosphatase that regulates endosomal signaling and angiogenesis. Paladin was localized to the endosomal and Golgi compartments, and interacted with vascular endothelial growth factor receptor 2 (VEGFR2) in vitro and in vivo. Loss of Paladin resulted in increased internalization of the receptor, over-activation of extracellular regulated kinase, and hypersprouting of endothelial cells in the developing retina of mice. These findings suggest that inhibition of Paladin, or other endosomal PI(4,5)P2 phosphatases, could be exploited to modulate VEGFR2 signaling and angiogenesis, when direct and full inhibition of the receptor is not desirable.

cell biology↗

bioRxiv2018

Fibrocyte accumulation in bronchi: a cellular hallmark of COPD

BackgroundThe remodeling mechanism and cellular players causing persistent airflow limitation in chronic obstructive pulmonary disease (COPD) remain largely elusive. We have recently demonstrated that circulating fibrocytes, a rare population of fibroblast-like cells produced by the bone marrow stroma, are increased in COPD patients during an exacerbation. It remains, however, unclear, whether fibrocytes are present in bronchial tissue of COPD patients.\n\nObjectiveWe aimed to quantify fibrocytes density in bronchial specimens from both control subjects and COPD patients, and to define associations with clinical, functional and computed tomography relevant parameters.\n\nMethods17 COPD patients and 25 control subjects with normal lung function testing and no chronic symptoms, all of them requiring thoracic surgery, were recruited. LFT and CT-scan were performed before surgery. Using co-immunostaining and image analysis, we identify CD45+ FSP1+ cells as tissue fibrocytes and quantify their density in distal and proximal bronchial specimens from the whole series.\n\nResultsHere, we demonstrate that fibrocytes are increased in both distal and proximal tissue specimens of COPD patients, compared to those of controls. The density of fibrocytes is negatively correlated with lung function parameters, such as FEV1 and FEV1/FVC, and positively with bronchial wall thickness assessed by CT scan. High density of distal bronchial fibrocytes predicts presence of COPD with a sensitivity of 83% and a specificity of 70%.\n\nConclusionsOur results thus suggest that recruitment of fibrocytes in the bronchi may participate to lung function decline during COPD progression.\n\nClinical ImplicationsHigh density of tissue fibrocytes is associated with a deteriorated lung function and an increase in airway wall thickness. A low density tissue fibrocytes virtually eliminates the presence of COPD.\n\nCapsule summaryBlood fibrocytes assessed during exacerbation is a predictor of mortality in COPD. This study shows an increase of bronchial fibrocytes, that is associated with lower lung function, increased bronchial thickness and air trapping in COPD.

physiology↗