Miracle-dz/UniFAR-FTUs huggingface dataset:
Local and Global Measures of Information Storage for the Assessment of Heartbeat-Evoked Cortical Responses

Objective Brain-heart interactions involve bidirectional effects produced by bottom-up input at each heartbeat, and top-down neural regulatory responses of the brain. While the cortical processing of the heartbeat is usually investigated through the analysis of the Heartbeat Evoked Potential, in this study we propose an alternative approach based on the variability in the predictability of the brain dynamics induced by the heartbeat. Methods In a group of eighteen subjects in whom simultaneous recording of the electroencephalogram (EEG) and electrocardiogram was performed in a resting-state, we analyzed the temporal profile of the local Information Storage (IS) to detect changes in the regularity of EEG signals in time windows associated with different phases of the cardiac cycle at rest. Results The average values of the local IS were significantly higher in the parieto-occipital areas of the scalp, suggesting an activation of the Default Mode Network, regardless of the cardiac cycle phase. In contrast, the variability of the local IS showed marked differences across the cardiac cycle phases. Conclusion Our results suggest that cardiac activity influences the predictive information of EEG dynamics differently in the various phases of the cardiac cycle. Significance The variability of local IS measures can represent a useful index to identify spatio-temporal dynamics within the neurocardiac system, which generally remain overlooked by the more widely employed global measures.
Quantifying and predicting chromatic thresholds

Perceptual thresholds measured in the two-dimensional chromatic diagram are elliptical in shape. Across different parts of the chromatic diagram, these ellipses vary in their sizes, their tilting angles, and in how much they elongate. Overall, the chromatic thresholds exhibit intriguing patterns that were reflected in McAdam’s measurements in 1942. Previously, da Fonseca and Samengo (2016) used a neural model combined with Fisher information (a quantification of perceptual thresholds) to predict the pattern of chromatic thresholds measured in human observers. The model assumes linear cone responses paired with Poisson noise. I furthered the analysis, and studied two additional aspects of chromatic perception. First, I quantified how the pattern of chromatic thresholds vary when the proportion of three cone types (short-, mid-, and long-wavelength) varies. This analysis potentially leads to efficient estimation of thresholds across the chromatic diagram. Second, I analyzed to what extent the assumption of Poisson noise contributes to the threshold predictions. Surprisingly, eliminating Poisson noise betters the model prediction. So in addition to Poisson noise, I examined three alternative noise assumptions, and achieved improved predictions to MacAdam’s data. At last, I examined an application using the improved model-predictions. The total number of cones, as well as the proportion of S cone vary across retinal eccentricities. I showed that these two variations predict chromatic threshold patterns across retinal eccentricities are drastically different.
Midbrain encodes sound detection behavior without auditory cortex

Hearing involves analyzing the physical attributes of sounds and integrating the results of this analysis with other sensory, cognitive and motor variables in order to guide adaptive behavior. The auditory cortex is considered crucial for the integration of acoustic and contextual information and is thought to share the resulting representations with subcortical auditory structures via its vast descending projections. By imaging cellular activity in the corticorecipient shell of the inferior colliculus of mice engaged in a sound detection task, we show that the majority of neurons encode information beyond the physical attributes of the stimulus and that the animals’ behavior can be decoded from the activity of those neurons with a high degree of accuracy. Surprisingly, this was also the case in mice in which auditory cortical input to the midbrain had been removed by bilateral cortical lesions. This illustrates that subcortical auditory structures have access to a wealth of non-acoustic information and can, independently of the auditory cortex, carry much richer neural representations than previously thought.
Multi-study fMRI outlooks on subcortical BOLD responses in the stop-signal paradigm

This study investigates the functional network underlying response inhibition in the human brain, particularly the role of the basal ganglia in successful action cancellation. Functional magnetic resonance imaging (fMRI) approaches have frequently used the stop-signal task (SST) to examine this network. We merge five such datasets, using a novel aggregatory method allowing the unification of raw fMRI data across sites. This meta-analysis, along with other recent aggregatory fMRI studies, do not find evidence for the innervation of the hyperdirect or indirect cortico-basal-ganglia pathways in successful response inhibition. What we do find, is large subcortical activity profiles for failed stop trials. We discuss possible explanations for the mismatch of findings between the fMRI results presented here and results from other research modalities that have implicated nodes of the basal ganglia in successful inhibition. We also highlight the substantial effect smoothing can have on the conclusions drawn from task-specific GLMs. First and foremost, this study presents a proof of concept for meta-analytical methods that enable the merging of extensive, unprocessed or unreduced datasets. It demonstrates the significant potential that open-access data sharing can offer to the research community. With an increasing number of datasets being shared publicly, researchers will have the ability to conduct meta-analyses on more than just summary data.
Treatment of set order relations by means of a nonlinear scalarization functional: a full characterization

In this paper, we show how a nonlinear scalarization functional can be used in order to characterize several well-known set order relations and which thus plays a key role in set optimization. By means of this functional, we derive characterizations for minimal elements of set-valued optimization problems using a set approach. Our methods do not rely on any convexity assumptions on the considered sets. Furthermore, we develop a derivative-free descent method for set optimization problems without convexity assumptions to verify the usefulness of our results.
Multistability in neural systems with random cross-connections

Neural circuits with multiple discrete attractor states could support a variety of cognitive tasks according to both empirical data and model simulations. We assess the conditions for such multistability in neural systems using a firing rate model framework, in which clusters of similarly responsive neurons are represented as single units, which interact with each other through independent random connections. We explore the range of conditions in which multistability arises via recurrent input from other units while individual units, typically with some degree of self-excitation, lack sufficient self-excitation to become bistable on their own. We find many cases of multistability—defined as the system possessing more than one stable fixed point—in which stable states arise via a network effect, allowing subsets of units to maintain each others' activity because their net input to each other when active is sufficiently positive. In terms of the strength of within-unit self-excitation and standard deviation of random cross-connections, the region of multistability depends on the response function of units. Indeed, multistability can arise with zero self-excitation, purely through zero-mean random cross-connections, if the response function rises supralinearly at low inputs from a value near zero at zero input. We simulate and analyze finite systems, showing that the probability of multistability can peak at intermediate system size, and connect with other literature analyzing similar systems in the infinite-size limit. We find regions of multistability with a bimodal distribution for the number of active units in a stable state. Finally, we find evidence for a log-normal distribution of sizes of attractor basins, which produces Zipf’s Law when enumerating the proportion of trials within which random initial conditions lead to a particular stable state of the system.
The proprotein convertase BLI-4 promotes collagen secretion during assembly of the Caenorhabditis elegans cuticle

Some types of collagens, including transmembrane MACIT collagens and C. elegans cuticle collagens, are N-terminally cleaved at a dibasic site that resembles the consensus for furin or other proprotein convertases of the subtilisin/kexin (PCSK) family. Such cleavage may release transmembrane collagens from the plasma membrane and affect extracellular matrix assembly or structure. However, the functional consequences of such cleavage are unclear and evidence for the role of specific PCSKs is lacking. Here, we used endogenous collagen fusions to fluorescent proteins to visualize the secretion and assembly of the first collagen-based cuticle in C. elegans and then tested the role of the PCSK BLI-4 in these processes. Unexpectedly, we found that cuticle collagens SQT-3 and DPY-17 are secreted into the extraembryonic space several hours before cuticle matrix assembly. Furthermore, this early secretion depends on BLI-4/PCSK; in bli-4 and cleavage-site mutants, SQT-3 and DPY-17 are not efficiently secreted and instead form large intracellular aggregates. Their later assembly into cuticle matrix is reduced but not entirely blocked. These data reveal a role for collagen N-terminal processing in intracellular trafficking and in the spatial and temporal restriction of matrix assembly in vivo. Our observations also prompt a revision of the classic model for C. elegans cuticle matrix assembly and the pre-cuticle-to-cuticle transition, suggesting that cuticle layer assembly proceeds via a series of regulated steps and not simply by sequential secretion and deposition.
Impaired cerebellar plasticity hypersensitizes sensory reflexes in SCN2A-associated ASD

Children diagnosed with autism spectrum disorder (ASD) commonly present with sensory hypersensitivity, or abnormally strong reactions to sensory stimuli. Such hypersensitivity can be overwhelming, causing high levels of distress that contribute markedly to the negative aspects of the disorder. Here, we identify the mechanisms that underlie hypersensitivity in a sensorimotor reflex found to be altered in humans and in mice with loss-of-function in the ASD risk-factor gene SCN2A. The cerebellum-dependent vestibulo-ocular reflex (VOR), which helps maintain one’s gaze during movement, was hypersensitized due to deficits in cerebellar synaptic plasticity. Heterozygous loss of SCN2A-encoded NaV1.2 sodium channels in granule cells impaired high-frequency transmission to Purkinje cells and long-term potentiation, a form of synaptic plasticity important for modulating VOR gain. VOR plasticity could be rescued in adolescent mice via a CRISPR-activator approach that increases Scn2a expression, highlighting how evaluation of simple reflexes can be used as quantitative readout of therapeutic interventions.
Spatially and temporally distinct patterns of expression for VPS10P domain receptors in human cerebral organoids

Vacuolar protein sorting 10 protein (VPS10P) domain receptors are a unique class of intracellular sorting receptors that emerge as major risk factors associated with psychiatric and neurodegenerative diseases, including bipolar disorders, autism, schizophrenia, as well as Alzheimer’s disease and frontotemporal dementia. Yet, the lack of suitable experimental models to study receptor functions in the human brain has hampered elucidation of receptor actions in brain disease. Here, we have adapted protocols in human cerebral organoids to the detailed characterization of VPS10P domain receptor expression during development and in mature brain tissue, including single-cell RNA sequencing. Our studies uncovered spatial and temporal patterns of expression unique to individual receptor species in the human brain. While SORL1 expression is abundant in stem cells and SORCS1 peaks at onset of neurogenesis, SORT1 and SORCS2 show increasing expression with maturation of neuronal and non-neuronal cell types, arguing for distinct functions in development versus the adult brain. In neurons, subcellular localization also distinguishes between two types of receptors, either mainly localized to the cell soma (SORL1 and SORT1) or also to neuronal projections (SORCS1 and SORCS2), suggesting divergent functions in protein sorting between Golgi and the endo-lysosomal system or along axonal and dendritic tracks. Taken together, our findings provide an important resource concerning temporal, spatial, and subcellular patterns of VPS10P domain receptor expression in cerebral organoids for further elucidation of receptor (dys)functions causative of behavioral and cognitive defects of the human brain.
Marked irregular myofiber shape is a hallmark of human skeletal muscle ageing and is reversed by heavy resistance training

Background Age-related loss of strength is disproportionally greater than the loss of mass, suggesting maladaptations in the neuro-myo-tendinous system. Myofibers are often misshaped in aged and diseased muscle, but systematic analyses of large sample sets are lacking. Our aim was to investigate myofiber shape in relation to age, exercise, myofiber type, species, and sex. Methods Previously collected vastus lateralis muscle biopsies (n=265) from 197 males and females, covering an age-span of 20 to 97 years, were examined. The gastrocnemius and soleus muscles of 7 C57BL/6 mice were also examined. Immunofluorescence and ATPase stainings of muscle cross-sections were used to measure myofiber cross-sectional area (CSA) and perimeter, from which a shape factor index (SFI) was calculated in a fiber type specific manner (type I and II in humans; type I, IIa, IIx and IIb in mice). Heavy resistance training (RT) was performed 3 times per week for 3-4 months by a subgroup (n=59). Correlation analyses were performed comparing SFI and CSA with age, muscle mass, maximal voluntary contraction (MVC), rate of force development (RFD), and specific force (MVC/muscle mass). Results In human muscle, SFI was positively correlated with age for both type I (R2=0.20) and type II (R2=0.38) myofibers. When subjects were separated into age cohorts, SFI was lower for type I (p<0.001) and II (p<0.001) myofibers in Young (20-36) compared to Old (60-80), and higher for type I (p<0.05) and II (p<0.001) myofibers in the Oldest Old (>80) compared to Old. The increased SFI in old muscle was observed in myofibers of all sizes. Within all three age cohorts, type II myofibers SFI was higher than for type I myofibers (p<0.001), which was also the case in mice muscles (p<0.001). Across age cohorts, there was no difference between males and females in SFI for either type I (p=0.496/0.734) or II (p=0.176/0.585) myofibers. Multiple linear regression revealed that SFI, after adjusting for age and myofiber CSA, has independent explanatory power for 8 out of 10 indices of muscle mass and function. RT reduced SFI of type II myofibers in both Young and Old (p<0.001). Conclusions Here, we identify type I and II myofiber shape in humans and mice as a hallmark of muscle ageing, that independently predicts volumetric and functional assessments of muscle health. RT reverts the shape of type II myofibers, indicating that lack of neuromuscular activation might lead to myofiber deformity.
Negative cell cycle regulation by Calcineurin is necessary for proper beta cell regeneration in zebrafish

Stimulation of pancreatic beta cell regeneration could be a therapeutic lead to treat diabetes. Unlike humans, the zebrafish can efficiently regenerate beta cells, notably from ductal pancreatic progenitors. To gain insight into the molecular pathways involved in this process, we established the transcriptomic profile of the ductal cells after beta cell ablation in the adult zebrafish. These data highlighted the protein phosphatase calcineurin as a new potential modulator of beta cell regeneration. We showed that calcineurin overexpression abolished the regenerative response, leading to glycemia dysregulation. On the opposite, calcineurin inhibition increased ductal cell proliferation and subsequent beta cell regeneration. Interestingly, the enhanced proliferation of the progenitors was paradoxically coupled with their exhaustion. This suggests that the proliferating progenitors are next entering in differentiation. Calcineurin appears as a guardian which prevents an excessive progenitor proliferation to preserve the pool of progenitors. Altogether, our findings reveal calcineurin as a key player in the balance between proliferation and differentiation to enable a proper beta cell regeneration.
Long-term cytotoxic NK cells with broad anti-tumour capacity proliferate selectively, without exhaustion, after BCG priming and extremely low doses of cytokines

Background: Natural killer (NK) cell-based immunotherapies, currently under investigation, appear to be safe, efficient treatments in patients with haematological tumours. Nevertheless, the short-lived nature of these cells combined with the need to infuse large number of cells for efficient tumour elimination represent important challenges for the development of NK cell-based therapies. Although NK cell anti-tumour activity is regulated by cytokines, constant stimulation together with the immunosuppressive tumour environment can result in NK cell exhaustion. Therefore, improved approaches to produce highly cytotoxic and longer-lived NK cells are of considerable clinical interest. Methods: Peripheral blood mononuclear cells (PBMC) are primed in vitro with a pulse of either Bacillus Calmette-Guérin (BCG) vaccine or a cell wall extract of M. bovis, followed by weekly stimulations with low doses of IL12, 15 and 21. The phenotype and anti-tumour fitness of the activated NK cell culture were examined using scRNA-seq, flow cytometry and functional assays, including degranulation, specific cytotoxicity and IFNγ release. Results: we describe a novel strategy for the generation of long-lived activated NK cells capable of killing a broad range of solid tumours. A unique subset of cytotoxic NK cells (CD56high CD16+ NKG2A+) specifically proliferated in vitro, and was further expanded without functional exhaustion under minimal survival cytokine combinations. Mycobacterial cell-wall fractions also activated NK cells that recognised tumours efficiently, and proliferated well, and this approach has the advantage that no live bacteria are present in the cultures. Conclusions: We propose that BCG-priming to expand anti-tumour NK cells, without cell sorting, could be a scalable and economical basis for the development of safe and universal cellular immunotherapies against solid tumours. Key messages Adoptive therapy with sorted NK cells grown in IL12, 15, 18 are being tested in clinical trials, but are only efficient for haematological tumours. In addition, their survival in vivo is limited. Here, we define culture conditions that drive the selective proliferation of long-lived natural killer (NK) cells, without the need of cell sorting, in minimal doses of cytokines, after priming with BCG or mycobacteria components. BCG-primed NK cells grow and maintain effective cytotoxic function against a variety of solid tumours in vitro, without exhaustion for at least 28 days of culture. This new approach provides the basis for the generation of innate adoptive cell therapy tools.
Dopamine Alters the Effect of Brain Stimulation on Decision-Making

Noninvasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), show promise in treating a range of psychiatric and neurologic conditions. However, optimization of such applications requires a better understanding of how tDCS alters cognition and behavior. Existing evidence implicates dopamine in tDCS alterations of brain activity and plasticity; however, there is as yet no causal evidence for a role of dopamine in tDCS effects on cognition and behavior. Here, in a preregistered, double-blinded study, we examined how pharmacologically manipulating dopamine altered the effect of tDCS on the speed–accuracy trade-off, which taps ubiquitous strategic operations. Cathodal tDCS was delivered over the left prefrontal cortex and the superior medial frontal cortex before participants (N = 62, 24 males, 38 females) completed a dot-motion task, making judgments on the direction of a field of moving dots under instructions to emphasize speed, accuracy, or both. We leveraged computational modeling to uncover how our interventions altered latent decisional processes driving the speed–accuracy trade-off. We show that dopamine in combination with tDCS (but not tDCS alone nor dopamine alone) not only impaired decision accuracy but also impaired discriminability, which suggests that these manipulations altered the encoding or representation of discriminative evidence. This is, to the best of our knowledge, the first direct evidence implicating dopamine in the way tDCS affects cognition and behavior. SIGNIFICANCE STATEMENT tDCS can improve cognitive and behavioral impairments in clinical conditions; however, a better understanding of its mechanisms is required to optimize future clinical applications. Here, using a pharmacological approach to manipulate brain dopamine levels in healthy adults, we demonstrate a role for dopamine in the effects of tDCS in the speed–accuracy trade-off, a strategic cognitive process ubiquitous in many contexts. In doing so, we provide direct evidence implicating dopamine in the way tDCS affects cognition and behavior.
Whole Genome Sequencing Reveals Autooctoploidy in the Chinese Sturgeon and its Evolutionary Trajectories

The Order Acipenseriformes, which include sturgeons and paddlefishes, represent “living fossils” with complex genomes that are good models for understanding whole genome duplication (WGD) and ploidy evolution in fishes. Here we sequenced and assembled the first high-quality chromosome-level genome for the complex octoploid Acipenser sinensis (Chinese sturgeon), a critically endangered species that also represents a poorly understood ploidy group in Acipenseriformes. Our results show that A. sinensis is a complex autooctoploid species containing four kinds of octovalents (8 n), a hexavalent (6 n), two tetravalents (4 n), and a divalent (2 n). We propose based on an analysis taking into account delayed rediploidization that its octoploid genome composition results from two rounds of homologous whole genome duplications (WGDs), and further provide insight into the timing of its ploidy evolution. This study provides the first octoploid genome resource of Acipenseriformes for understanding ploidy composition and evolutionary trajectories of polyploidy fishes.