HAL-Pasteur
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The Geometry of Layer 2/3 Cortical Sound Processing in Slow Wave Sleep
No full textInternational audienceDuring wake, sound-evoked and spontaneous neural activity of the auditory cortex evolves in distinct subspaces, whereas anesthesia disrupts sound responses and merges these spaces. To evaluate if similar modifications of sound representation geometry explain sensory disconnection during sleep, large neural populations of the mouse auditory cortex are followed across slow-wave sleep and wakefulness. It is observed that sleep dampens sound responses but preserves the geometry of sound representations such that they remain separate from spontaneous activity. Moreover, response dampening is strongly coordinated across neurons and varied throughout sleep, spanning from fully preserved response patterns to population response failures on a fraction of sound presentations. These failures rarely occurred in wakefulness and are more common during high spindle-band activity. Therefore, in sleep, the auditory system preserves sound feature selectivity up to the cortex for detailed acoustic surveillance but concurrently implements an intermittent gating mechanism leading to local sensory disconnections.</div
Functional connectivity of the amygdala subnuclei in various mood states of bipolar disorder
No full textInternational audienceAmygdala functional dysconnectivity lies at the heart of the pathophysiology of bipolar disorder (BD). Recent preclinical studies suggest that the amygdala is a heterogeneous group of nuclei, whose specific connectivity could drive positive or negative emotional valence. We investigated functional connectivity (FC) changes within these circuits emerging from each amygdala's subdivision in 127 patients with BD in different mood states and 131 healthy controls (HC), who underwent resting-state functional MRI. FC was evaluated between lateral and medial nuclei of amygdalae, and key subcortical regions of the emotion processing network: anterior and posterior parts of the hippocampus, and core and shell parts of the nucleus accumbens. FC was compared across groups, and subgroups of patients depending on their mood states, using linear mixed models. We also tested correlations between FC and depression (MADRS) and mania (YMRS) scores. We found no difference between the whole sample of BD patients vs. HC but a significant correlation between MADRS and right lateral amygdala /right anterior hippocampus, right lateral amygdala/right posterior hippocampus and right lateral amygdala/left anterior hippocampus FC (r = -0.44, r = -0.32, r = -0.27, respectively, all pFDR<0.05). Subgroup analysis revealed decreased right lateral amygdala/right anterior hippocampus and right lateral amygdala/right posterior hippocampus FC in depressed vs. non-depressed patients and increased left medial amygdala/shell part of the left nucleus accumbens FC in manic vs non-manic patients. These results demonstrate that acute mood states in BD concur with FC changes in individual nuclei of the amygdala implicated in distinct emotional valence processing. Overall, our data highlight the importance to consider the amygdala subnuclei separately when studying its FC patterns including patients in distinct homogeneous mood states
Enhanced detection of low-expressed miRNAs in Leishmania -infected macrophages through RNA fractionation and RT-qPCR optimization
No full textMicroRNAs (miRNAs) play critical roles in regulating host responses to Leishmania infections, yet accurate detection of low-abundance miRNAs remains challenging. This study evaluated the impact of RNA fractionation and RT-qPCR protocol optimization on miRNA quantification in Leishmaniaamazonensis-infected murine macrophages. Using a panel of nine infection-associated miRNAs, we compared small RNA and total RNA fractions for their ability to detect weakly expressed targets. Small RNA consistently provided greater sensitivity and specificity, particularly when combined witha modified RT-qPCR protocol. These findings underscore the importance of RNA preparation methods for studying miRNA dynamics in infectious disease contexts and support improved approaches for detecting biologically relevant, low-expressed miRNAs
Leishmania amazonensis controls macrophage-regulated cell death to establish chronic infection in vitro and in vivo
No full textPathogenic protists of the genus Leishmania have evolved various strategies to exploit macrophages as host cells and subvert their immuno-metabolic functions to favour intracellular parasite survival. Surprisingly little is known on how Leishmania affects regulated cell death (RCD) pathways of its host cell, even though increased survival of in vitro infected macrophages has been reported, and chronic macrophage infection in vivo causes the devastating immunopathologies of leishmaniasis. To overcome this limitation and gain first systems-level insight into the interaction between intracellular Leishmania and the host cell RCD pathways, including apoptosis, pyroptosis and necroptosis, we applied transcriptomic analyses on L. amazonensis-infected, primary macrophages (termed LIMs) and used YO-PRO-1 to monitor cell death by fluorescent microscopy. RNAseq analyses at day 3 post-infection (PI) revealed dichotomic dysregulation of more than 60% of RCD-related genes in LIMs, characterized by up-regulation of anti-RCD and down-regulation of pro-RCD markers, including key regulators common to the three forms of cell death such as casp8, fadd, tradd, tnfaip3, tax1bp1, birc3, and itch. This profile correlated with expression changes of transcription factors known to regulate RCD, including AP1 and NF-κB family members, pparγ and cebpβ. Consequently, LIMs showed remarkable longevity in culture for at least 50 days, despite a constant increase of parasite burden to about 100 parasites per cell, while non-infected cells were cleared from the culture in just a few days. Longitudinal expression analysis of LIMs at days 0, 3, 15, and 30 PI by RT-qPCR confirmed stable maintenance of this high longevity profile with the dichotomic decrease and increase of RCD-activators and -inhibitors, respectively. LIMs further showed significant resistance to RCD-inducing signals compared to non-infected cells, including CSF-1 deprivation (intrinsic apoptosis), actinomycin D treatment (extrinsic apoptosis), LPS/ATP stimulation (pyroptosis). Significantly, we extended the anti-RCD expression pattern and RCD resistance phenotype to L. amazonensis-infected macrophages recovered from lesions, thus validating our long-term in vitro infection system as an easily accessible model to study chronic macrophage infection. In conclusion, our analyses firmly document the pan-anti RCD effect of L. amazonensis on its macrophage host cell in vitro and in vivo and shed important new light on mechanisms underlying Leishmania chronic infection
Clinical Manifestations of Emerging Trichosporon spp. Infections, France
No full textInternational audienceFungi in the family Trichosporonaceae are rarely involved in invasive disease but are frequently associated with colonization or respiratory allergic infection. Trichosporonaceae exhibit intrinsic resistance to echinocandin antimicrobial drugs, posing challenges for treatment and contributing to high mortality rates. We complied a nationwide analysis of 112 cases of invasive disease caused by Trichosporon spp. and related fungi, diagnosed in France over 20 years, that combined clinical data, susceptibility profiles, and molecular identification. We identified 12 species; T. asahii was the most common species recovered, and the new species T. austroamericanum was next. Comparison of clinical data highlighted species and genotypic differences, such as a much higher proportion of children infected by T. asahii and major differences in antimicrobial drug susceptibility. Correct identification is not only of epidemiologic interest but also necessary for patient management because of the varying clinical and microbiological characteristics found in different species
Long-term genetic mark and recapture in Astyanax mexicanus cave populations: demographic inferences and conservation issues
No full textInternational audienceThe cave populations of Astyanax mexicanus in northeastern Mexico are the subject of intensive study as a model for investigating evolutionary processes in subterranean environments. Investigating key evolutionary questions alongside conservation challenges requires a well-defined demographic framework. However, few estimates of population sizes have been obtained. In this study, we used genetic identification of cavefish individuals captured at various time intervals, ranging from a few days to several years, and in multiple caves, to gain insights into population size dynamics, population structure, and connectivity. We used 18 to 24 microsatellite markers to genotype and identify unambiguously 702 fish from six caves and several surface locations. The genetic distance between sampled fish, as well as short-term and long-term recaptures of cavefish, demonstrate that the most studied and sampled population, La Cueva de El Pachón, is small (comprising a few hundred individuals) and isolated. In contrast, populations in La Cueva de Los Sabinos and in El Sótano de Las Piedras, which we demonstrate belong to a well-connected cave cluster, could be larger, numbering in the thousands. At a larger geographical scale, our data suggest that the distribution of A. mexicanus cave populations in groundwater can be best described as a poorly connected network of oases within a karst desert
Semi-automated Detection of Late Cytokinetic Bridges
No full textInternational audienceDuring cytoplasmic division, the intercellular bridge is formed with a central midbody. In our opinion, more tools are required for investigation of the late molecular events leading to cytokinetic abscission. In this chapter, we briefly review the many available methods to screen for cytokinetic defects and present a protocol for image-based detection of late cytokinetic bridges. A simple immunofluorescence staining of the fixed cytoplasms, nuclei, and the midbodies, analyzed with tailored software, can reproducibly estimate the frequency of intercellular bridges. Here, we describe data collection and analysis in single cells upon inhibition by RNA interference using fluorescence microscopy
Intermittent antibiotic exposure of Escherichia coli biofilms drives resistance in catheter-associated infection models
No full textInternational audienceThe use of antibiotic lock therapy (ALT) to protect catheters from infection is still being debated due to its inconsistent effectiveness and the potential risk of promoting antibiotic resistance. Using an in vitro infection model of a pediatric venous access port, we demonstrated that 10 days of continuous therapy eradicates Escherichia coli biofilms in vitro without the emergence of antibiotic resistance. By contrast, an 8-h intermittent therapy used for infected parenteral nutrition patients rapidly selected low-level amikacin-resistant mutants both in vitro and in vivo in a clinically relevant rat model, primarily due to convergent fusA , sbmA , and cpxA mutations. Our findings indicate that intermittent dosing generates pulsed selective pressure, favoring the development of resistance mutants within spatially structured biofilm communities. This suggests that biofilms may act as evolutionary incubators, in which medical interventions could unintentionally influence adaptation outcomes. Furthermore, the low-level resistance developing in treated biofilms may be overlooked in clinical settings and contribute to the selection of high-level resistant mutants. Our study, therefore, underscores that, in addition to dosing, optimizing the timing of antimicrobial treatment could mitigate the emergence of resistance. These principles are applicable beyond catheters to any biofilm-related infections where short-term antibiotic exposure may impact microbial community adaptation
Invariant non-equilibrium dynamics of transcriptional regulation optimize information flow
No full textEukaryotic gene regulation is based on stochastic yet controlled promoter switching, during which genes transition between transcriptionally active and inactive states. Despite the molecular complexity of this process, recent studies reveal a surprising invariance of the "switching correlation time" (), which characterizes promoter activity fluctuations, across gene expression levels in diverse genes and organisms. A biophysically plausible explanation for this invariance remains missing. Here, we show that this invariance imposes stringent constraints on minimal yet plausible models of transcriptional regulation, requiring at least four system states and non-equilibrium dynamics that break detailed balance. Using Bayesian inference on Drosophila gap gene expression data, we demonstrate that such models (i) accurately reproduce the observed -invariance; (ii) remain robust to parameter perturbations; and (iii) maximize information transmission from transcription factor concentration to gene expression. These findings suggest that eukaryotic gene regulation has evolved to balance precision with reaction rate and energy dissipation constraints, favoring non-equilibrium architectures for optimal information transmission
Neuro-oscillatory models of cortical speech processing
No full textInternational audienceIn this review, we examine computational models that explore the role of neural oscillations in speech perception, spanning from early auditory processing to higher cognitive stages. We focus on models that use rhythmic brain activities, such as gamma, theta, and delta oscillations, to encode phonemes, segment speech into syllables and words, and integrate linguistic elements to infer meaning. We analyze the mechanisms underlying these models, their biological plausibility, and their potential applications in processing and understanding speech in real time, a computational feature that is achieved by the human brain but not yet implemented in speech recognition models. Real-time processing enables dynamic adaptation to incoming speech, allowing systems to handle the rapid and continuous flow of auditory information required for effective communication, interactive applications, and accurate speech recognition in a variety of real-world settings. While significant progress has been made in modeling the neural basis of speech perception, challenges remain, particularly in accounting for the complexity of semantic processing and the integration of contextual influences. Moreover, the high computational demands of biologically realistic models pose practical difficulties for their implementation and analysis. Despite these limitations, these models provide valuable insights into the neural mechanisms of speech perception. We conclude by identifying current limitations, proposing future research directions, and suggesting how these models can be further developed to achieve a more comprehensive understanding of speech processing in the human brain