Miracle-dz/UniFAR-FTUs huggingface dataset:
The early adolescent brain on music: Analysis of functional dynamics reveals engagement of orbitofrontal cortex reward system

Music listening plays a pivotal role for children and adolescents, yet surprisingly few neuroimaging studies have studied the underlying functional dynamics. We used functional magnetic resonance imaging to scan 17 preadolescents aged 10-11 years old while listening to music. We subsequently tracked the occurrence of functional brain networks over time by using a recent method that detects recurrent BOLD phase-locking states: the Leading Eigenvector Dynamics Analysis (LEiDA). In particular, we compared the probabilities of occurrence and switching profiles of different patterns of BOLD phase-locking between music and no music. Moreover, we used an adapted version of the Barcelona Music Reward Questionnaire (BMRQ) to measure the music reward sensitivity of the participants. Our results showed significantly increased occurrence of a BOLD phase-locking pattern during music listening compared to no music, characterized by a phase-shift in the BOLD signals of the medial orbitofrontal and ventromedial prefrontal cortices – a brain subsystem associated to reward processing – from the rest of the brain. Moreover, we observed a significantly higher probability of switching to this pattern while listening to music. We also found a positive correlation between the individual musical reward sensitivity and the tendency to switch to this reward state during music. Our findings highlight the involvement of a brain subsystem involved in hedonic processing during music listening in the early adolescent brain. These results offer novel insight into the neural underpinnings of musical reward in early adolescence and may help us to understand the importance of music at this delicate age.
Phenome-scale causal network discovery with bidirectional mediated Mendelian randomization

Inference of directed biological networks from observational genomics datasets is a crucial but notoriously difficult challenge. Modern population-scale biobanks, containing simultaneous measurements of traits, biomarkers, and genetic variation, offer an unprecedented opportunity to study biological networks. Mendelian randomization (MR) has received attention as a class of methods for inferring causal effects in observational data that uses genetic variants as instrumental variables, but MR methods rely on assumptions that limit their application to complex traits at the biobank-scale. Moreover, MR estimates the total effect of one trait on another, which may be mediated by other factors. Biobanks include measurements of many potential mediators, in principle enabling the conversion of MR estimates into direct effects representing a causal network. Here, we show that this can be accomplished by a flexible two stage procedure we call bidirectional mediated Mendelian randomization (bimmer). First, bimmer estimates the effect of every trait on every other. Next, bimmer finds a parsimonious network that explains these effects using direct and mediated causal paths. We introduce novel methods for both steps and show via extensive simulations that bimmer is able to learn causal network structures even in the presence of non-causal genetic correlation. We apply bimmer to 405 phenotypes from the UK biobank and demonstrate that learning the network structure is invaluable for interpreting the results of phenome-wide MR, while lending causal support to several recent observational studies.
HNRNPM controls circRNA biogenesis and splicing fidelity to sustain prostate cancer cell fitness

Cancer cells are differentially dependent on the splicing machinery compared to normal untransformed cells. The splicing machinery thus represents a potential therapeutic target in cancer. To identify splicing factors important for prostate cancer cell (PCa) cell growth, we performed a parallel pooled shRNA screen on in vitro passaged cells and in vivo xenografted PCa tumor lines. Our screen revealed HNRNPM as a potential regulator of PCa cell growth. RNA- and eCLIP-sequencing data suggest that HNRNPM is bound to transcripts of key homeostatic genes and that loss of HNRNPM binding in a subset of these genes results in aberrant exon inclusion and exon back-splicing events in target transcripts. In both linear and circular mis-spliced transcripts, HNRNPM appears to preferentially bind to GU-rich elements in long flanking proximal introns. Mimicry of HNRNPM dependent linear splicing events using splice-switching antisense oligonucleotides (SSOs) was sufficient to inhibit cell growth in HNRNPM expressing cells. This suggests that prostate cancer cell dependence on HNRNPM is likely a result of mis-splicing of key homeostatic coding and non-coding genes. Taken together, our data reveal a role for HNRNPM in supporting prostate cancer cell fitness, and also as a potential therapeutic target in PCa.
Neural surprise in somatosensory Bayesian learning

Tracking statistical regularities of the environment is important for shaping human behavior and perception. Evidence suggests that the brain learns environmental dependencies using Bayesian principles. However, much remains unknown about the employed algorithms, for somesthesis in particular. Here, we describe the cortical dynamics of the somatosensory learning system to investigate both the form of the generative model as well as its neural surprise signatures. Specifically, we recorded EEG data from 40 participants subjected to a somatosensory roving-stimulus paradigm and performed single-trial modeling across peri-stimulus time in both sensor and source space. Our Bayesian model selection procedure indicates that evoked potentials are best described by a non-hierarchical learning model that tracks transitions between observations using leaky integration. From around 70ms post-stimulus onset, secondary somatosensory cortices are found to represent confidence-corrected surprise as a measure of model inadequacy. Primary somatosensory cortex is found to encode Bayesian surprise, reflecting model updating, from around 140ms. As such, this dissociation indicates that early surprise signals may control subsequent model update rates. In sum, our findings support the hypothesis that early somatosensory processing reflects Bayesian perceptual learning and contribute to an understanding of its precise mechanisms. Author summary Our environment features statistical regularities, such as a drop of rain predicting imminent rainfall. Despite the importance for behavior and survival, much remains unknown about how these dependencies are learned, particularly for somatosensation. As surprise signalling about novel observations indicates a mismatch between one’s beliefs and the world, it has been hypothesized that surprise computation plays an important role in perceptual learning. By analyzing EEG data from human participants receiving sequences of tactile stimulation, we compare different formulations of surprise and investigate the employed underlying learning model. Our results indicate that the brain estimates transitions between observations. Furthermore, we identified different signatures of surprise computation and thereby provide a dissociation of the neural correlates of belief inadequacy and belief updating. Specifically, early surprise responses from around 70ms were found to signal the need for changes to the model, with encoding of its subsequent updating occurring from around 140ms. These results provide insights into how somatosensory surprise signals may contribute to the learning of environmental statistics.
Balanced JAK/STAT signaling is critical to maintain the functional and structural integrity of the Drosophila respiratory epithelium

Signals mediated by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway play a central role in maintaining homeostasis in a multitude of tissues. A large number of studies have shown that this role is particularly prominent in the lungs. Deregulation of the JAK/STAT signaling pathway is causally linked with various, mostly chronic, lung diseases, including lung cancer, asthma, and chronic obstructive pulmonary disease. To elucidate the molecular framework that explains how deregulated JAK/STAT signaling gives rise to pathogenic states, we used the fruit fly Drosophila as a model. While the JAK/STAT pathway is characterized by high structural diversity and complexity in vertebrates, it is relatively simple in Drosophila. The JAK/STAT pathway was active in almost all respiratory epithelial cells of larvae and adult flies. Stressful stimuli, such as cigarette smoke, evoked strong and regionalized activation of the JAK/STAT pathway, which was most likely driven by the concurrently induced ligand Unpaired 2. Inhibition of JAK/STAT signaling induced apoptotic processes in epithelial cells. The aforementioned chronic lung diseases are associated with increased activity of the JAK/STAT pathway and are treated with specific JAK inhibitors. Therefore, we investigated the effects of increased JAK/STAT signaling in the respiratory epithelium of Drosophila. Ectopic activation of the JAK/STAT pathway led to premature death at the larval or pupal stage. Furthermore, it induced major structural changes in epithelial cells, which almost completely lost their typical characteristics. These structural changes led to considerable thickening of the epithelium, substantial narrowing of the air-conducting space, and disruption of the tracheal epicuticular structure. Pharmacological interference of JAK/STAT signaling reverted this phenotype. Activation of the JAK/STAT pathway also affected vesicle-mediated transport, which led to erroneous trafficking of typical junction proteins. In summary, these results demonstrate that balanced JAK/STAT signaling is essential for the normal functionality of the respiratory epithelium and thus the entire organ. A basal level of JAK/STAT signaling is required for cellular processes such as growth and division. However, chronic overactivation of this signaling leads to massive structural changes that are closely related to pathologies typically seen in chronic inflammatory lung diseases.
Spatio-temporal Characteristics of Noun and Verb Processing during Sentence Comprehension in the Brain

The human brain is very effective at integrating new words one by one into the composed representation of a sentence as it is read left-to-right. This raises the important question of what happens to the neural representations of words present earlier in the sentence? For example, do the strength of word representations encountered earlier on in the sentence remain constant or do they evolve as additional words are processed? Representation of words by neural activity in the brain has been the subject of several previous studies. We perform the experiment with a naturalistic task in which the subjects read simple active and passive sentences. Naturalistic studies have tended to explore words in isolation or in a very limited context (e.g., adjective-noun phrases). Representation of previously encountered words during incremental sentence reading, and how such representation evolve as more parts of a sentence are read, is a fundamental but unexplored problem – we take a first step in this direction. In particular, we examine the spatio-temporal characteristics of neural activity encoding nouns and verbs encountered in a sentence as it is read word-by-word. We use Magnetoencephalography (MEG) to passively observe neural activity, providing 1 ms temporal resolution. Our experiments reveal that nouns and verbs read early in the sentence have a varying influence on neural activity while reading subsequent words, decreasing and increasing at particular word positions in active and passively voiced sentences, with particularly important contributions to activity in frontal and temporal cortical regions. We find the noun and verb information to be decodable from the neural activity for several seconds after sentence reading has completed. Our exploration is also the first to study the effect of question-answering task on the neural representation of the words post-sentence. We are releasing our 300 sentence MEG dataset to encourage further research in this important area.
Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

Significance The accumulation of amyloid β (Aβ) in the brain appears to be a necessary event in the pathogenesis of Alzheimer’s disease (AD). However, processes linked to the endogenous regulation of Aβ production are still not completely understood. Here, the authors show that Aβ accumulation in neurons is tightly regulated by cholesterol synthesis and apoE transport from astrocytes. The study provides a molecular context for understanding the endogenous regulation of Aβ accumulation and why it correlates with AD. The tight regulation suggests that Aβ may perform an important cellular function. A complete understanding of the mechanism is likely necessary to predict whether the selective removal of Aβ has potential for a therapeutic benefit. Alzheimer’s disease (AD) is characterized by the presence of amyloid β (Aβ) plaques, tau tangles, inflammation, and loss of cognitive function. Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic risk factor for sporadic AD. In vitro evidence suggests that apoE links to Aβ production through nanoscale lipid compartments (lipid clusters), but its regulation in vivo is unclear. Here, we use superresolution imaging in the mouse brain to show that apoE utilizes astrocyte-derived cholesterol to specifically traffic neuronal amyloid precursor protein (APP) in and out of lipid clusters, where it interacts with β- and γ-secretases to generate Aβ-peptide. We find that the targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid and tau burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid clusters, where it interacts with α-secretase and gives rise to soluble APP-α (sAPP-α), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on α-, β-, and γ-secretase trafficking, suggesting that the ratio of Aβ to sAPP-α is regulated by the trafficking of the substrate, not the enzymes. We conclude that cholesterol is kept low in neurons, which inhibits Aβ accumulation and enables the astrocyte regulation of Aβ accumulation by cholesterol signaling.
Rapid screening and detection of inter-type viral recombinants using phylo-k-mers

Motivation Novel recombinant viruses may have important medical and evolutionary significance, as they sometimes display new traits not present in the parental strains. This is particularly concerning when the new viruses combine fragments coming from phylogenetically-distinct viral types. Here, we consider the task of screening large collections of sequences for such novel recombinants. A number of methods already exist for this task. However, these methods rely on complex models and heavy computations that are not always practical for a quick scan of a large number of sequences. Results We have developed SHERPAS, a new program to detect novel recombinants and provide a first estimate of their parental composition. Our approach is based on the precomputation of a large database of “phylogenetically-informed k-mers”, an idea recently introduced in the context of phylogenetic placement in metagenomics. Our experiments show that SHERPAS is hundreds to thousands of times faster than existing software, and enables the analysis of thousands of whole genomes, or long sequencing reads, within minutes or seconds, and with limited loss of accuracy. Availability and Implementation The source code is freely available for download at https://github.com/phylo42/sherpas Contact pardi@lirmm.fr, gllm.scholz@gmail.com Supplementary information Supplementary Materials are available here.
Endogenous neural stem cells modulate microglia and protect from demyelination

In response to corpus callosum (CC) demyelination, subventricular zone-derived neural progenitors (SVZdNP) are mobilized and generate new myelinating oligodendrocytes. Here, we examine the putative immunomodulatory properties of endogenous SVZdNP during demyelination in the cuprizone model. We observed that SVZdNP density is higher in the lateral and rostral CC regions that show weaker demyelination and is inversely correlated with activated microglia density and pro-inflammatory cytokines levels. Single-cell RNA-sequencing further revealed CC areas with high SVZdNP mobilization are enriched in a microglial cell subpopulation with immunomodulatory signature. We identified ligand/receptor couple MFGE8 (milk fat globule-epidermal growth factor-8)/integrin β3 as a ligand/receptor couple implicated in SVZdNP/microglia dialog. MFGE8 is highly enriched in immature SVZdNP mobilized to the demyelinated CC and promotes myelin debris phagocytosis in vitro. Altogether these results demonstrate that beyond their cell replacement capacity endogenous progenitors display immunomodulatory properties highlighting a new role for endogenous SVZdNP in myelin regeneration.
Glucocorticoid treatment exacerbates mycobacterial infection by reducing the phagocytic capacity of macrophages Glucocorticoids and zebrafish TB

Glucocorticoids are effective drugs for treating immune-related diseases, but prolonged therapy is associated with an increased risk of various infectious diseases, including tuberculosis. In this study, we have used a larval zebrafish model for tuberculosis, based on Mycobacterium marinum (Mm) infection, to study the effect of glucocorticoids. Our results show that the synthetic glucocorticoid beclomethasone increases the bacterial burden and the dissemination of a systemic Mm infection. The exacerbated Mm infection was associated with a decreased phagocytic activity of macrophages, higher percentages of extracellular bacteria, and a reduced rate of infected cell death, whereas the bactericidal capacity of the macrophages was not affected. The inhibited phagocytic capacity of macrophages was associated with suppression of the transcription of genes involved in phagocytosis in these cells. The decreased bacterial phagocytosis by macrophages was not specific for Mm, since it was also observed upon infection with Salmonella Typhimurium. In conclusion, our results show that glucocorticoids inhibit the phagocytic activity of macrophages, which may increase the severity of bacterial infections like tuberculosis. Summary statement Using a zebrafish tuberculosis model, we show that glucocorticoids decrease phagocytosis by macrophages, thereby increasing the bacterial burden. This may explain the glucocorticoid-induced increase in susceptibility to tuberculosis in humans.
A DEAD BOX RNA helicase from Medicago truncatula is hijacked by an RNA-binding effector from the root pathogen Aphanomyces euteiches to facilitate host infection

Microbial effectors from plant pathogens are molecules that target host components to facilitate colonization. While eukaryotic pathogens are virtually able to produce hundreds of effectors, the molecular mechanisms allowing effectors to promote infection are still largely unexplored. Here we show that the effector AeSSP1256 from the soilborne oomycete pathogen Aphanomyces euteiches is able to interact with plant RNA. Heterologous expression of AeSSP1256 delays Medicago truncatula host roots development and facilitate pathogen colonization. Transcriptomic analyses of AeSSP1256-expressing roots show a downregulation of genes implicated in ribosome biogenesis pathway. A yeast-two hybrid approach reveals that AeSSP1256 associates with a nucleolar L7 ribosomal protein and a M. truncatula RNA helicase (MtRH10) orthologous to the Arabidopsis RNA helicase RH10. Association of AeSSP1256 with MtRH10 impaired the capacity of MtRH10 to bind nucleic acids. Promoter:GUS composite plants revealed that MtRH10 is expressed preferentially in the meristematic root cells. Missense MtRH10 plants displayed shorter roots with developmental delay and are more susceptible to A. euteiches infection. These results show that the effector AeSSP1256 facilitates pathogen infection by causing stress on plant ribosome biogenesis and by hijacking a host RNA helicase involved in root development and resistance to root pathogens.
Identification of Retinal Ganglion Cell Types and Brain Nuclei expressing the transcription factor Brn3c/Pou4f3 using a Cre recombinase knock-in allele

Members of the POU4F/Brn3 transcription factor family have an established role in the development of retinal ganglion cell types (RGCs), the projection sensory neuron conveying visual information from the mammalian eye to the brain. Our previous work using sparse random recombination of a conditional knock-in reporter allele expressing Alkaline Phosphatase (AP) and intersectional genetics had identified three types of Pou4f3/Brn3c positive (Brn3c+) RGCs. Here, we describe a novel Brn3cCre mouse allele generated by serial Dre to Cre recombination. We use this allele to explore the expression overlap of Brn3c with Brn3a and Brn3b and the dendritic arbor morphologies and visual stimulus properties of Brn3c+ RGC types. Furthermore, we explore Brn3c-expressing brain nuclei. Our analysis reveals a much larger number of Brn3c+ RGCs and more diverse set of RGC types than previously reported. The majority of RGCs having expressed Brn3c during development are still Brn3c positive in the adult, and all of them express Brn3a while only about half express Brn3b. Intersection of Brn3b and Brn3c expression highlights an area of increased RGC density, similar to an area centralis, corresponding to part of the binocular field of view of the mouse. Brn3c+ neurons and projections are present in multiple brain nuclei. Brn3c+ RGC projections can be detected in the Lateral Geniculate Nucleus (LGN), Pretectal Area (PTA) and Superior Colliculus (SC) but also in the thalamic reticular nucleus (TRN), a visual circuit station that was not previously described to receive retinal input. Most Brn3c+ neurons of the brain are confined to the pretectum and the dorsal midbrain. Amongst theses we identify a previously unknown Brn3c+ subdivision of the deep mesencephalic nucleus (DpMe). Thus, our newly generated allele provides novel biological insights into RGC type classification, brain connectivity and midbrain cytoarchitectonic, and opens the avenue for specific characterization and manipulation of these structures.