Biology subjects

Pereira, M.

Publications and source records attributed to Pereira, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Supramodal Coding of Detection and Confidence in the Human Cortex

Perception is inherently multisensory, yet it remains unclear whether the brain detects stimuli and evaluates confidence in these detections using circuits shared across senses or circuits specific to each modality. Prior evidence is limited: scalp electrophysiology cannot localize where a shared code operates, whereas functional imaging cannot resolve its timing. We recorded intracranial activity (stereoelectroencephalography) in eight patients with epilepsy who performed a near-threshold audiovisual detection task in which they reported, on each trial, whether a visual, auditory, or audiovisual stimulus was present and rated their confidence, both overall and separately for each modality. Analyzing high-gamma activity at the single-channel and region-of-interest levels, we found that stimulus detection involved a broadly distributed, largely supramodal set of cortical regions responding regardless of modality, including the insula, dorsomedial prefrontal cortex, and superior temporal gyrus. Multivariate decoders trained to distinguish detected from undetected stimuli in one modality generalized to the other modality, indicating a shared detection code within these regions. Confidence relied on a more mixed architecture but was also substantially supramodal. Finally, the auditory cortex encoded confidence information about its non-preferred (visual) modality, with a similar effect in the visual cortex for auditory confidence, suggesting that the involvement of sensory cortices in confidence is not confined to its preferred input.

neuroscience↗

bioRxiv2026

Flexible route planning and rapid structure learning by mice in complex environments

Action selection using predictive models of the environment plays a fundamental role in human and animal behaviour, yet is poorly understood at circuit and algorithmic levels. Spatial navigation is an attractive domain for characterising how world models guide action selection. However spatial behaviours are shaped by multiple control systems including habits, vector-navigation using a Euclidean model of spatial relationships, and route planning using models of environment structure. Understanding how world models support navigation requires assays that dissociate control systems and decorrelate behavioural variables, while generating large datasets that allow precise quantification of brain-behaviour relationships. Here we developed and computationally optimised a behavioural assay to quantify flexible navigation using knowledge of environment structure. Mice navigated to visually cued goals in complex mazes, with randomised start and goal locations on each trial, generating thousands of non-repetitive goal-directed navigation trajectories. They navigated efficiently - strongly favouring options on the shortest path-to-goal, and learnt rapidly - demonstrating knowledge of maze structure from their first sessions in new environments. We anticipate the assay will be useful for characterising how world models support flexible behaviour.

animal behavior and cognition↗

bioRxiv2026

Identification of drug candidates for rescue of SOX17 gene targets in pulmonary arterial hypertension

BackgroundBoth rare and common variants in the SRY-Box Transcription Factor 17 (SOX17) locus are associated with pulmonary arterial hypertension (PAH). SOX17 dysregulation leads to pulmonary artery endothelial cell (PAEC) dysfunction and the obstructive remodelling that characterises PAH. HypothesisImpaired SOX17 expression contributes to the pathogenesis of PAH. Restoring the function of SOX17 or its downstream targets using compounds that mimic its transcriptomic signature will rescue PAEC dysfunction and prevent PAH development. Methods and ResultsWe defined thousands of genes with direct SOX17 genomic binding sites and identified important potential binding partners, including ETS-transcription factors such as ERG by ChIP-seq in PAECs. Through the integration of three PAEC RNA-seq datasets involving overexpression and silencing of SOX17, we defined a robust SOX17 transcriptomic signature. In PAH patients, circulating plasma protein levels of 10 SOX17 signature genes were associated with the SOX17 common risk variants. This included EFNB2 and UNC5B; knockdown of these genes altered the viability and apoptosis of PAECs in response to TNF treatment. The drug-transcriptome database Connectivity Map (CMap) was used to predict novel potential therapeutic compounds to correct the SOX17 transcriptomic signature. Five compounds were selected for in vitro testing and were able to partially reinstate SOX17 target gene expression in PAECs. One compound, BX-912, was selected for in vivo testing as it corrected the levels of multiple target genes, including suppressing Runt-related transcription factor-1 (RUNX1). BX-912 blocked the development of pulmonary hypertension in mice lacking the SOX17 enhancer associated with human disease. ConclusionWe have demonstrated the therapeutic potential of targeting SOX17 in PAH through correction of its gene targets, identifying BX-912 as a lead compound with in vivo efficacy.

pharmacology and toxicology↗

bioRxiv2026

Impaired SOX17 Expression Causes Endothelial Dysfunction and Pulmonary Arterial Hypertension by Insufficient Suppression of RUNX1

Genome-wide association studies have identified rare and common mutations associated with increased risk of pulmonary arterial hypertension (PAH), but the mechanism by which impaired SOX17 expression increases PAH risk is not known. Notably, SOX17 plays a critical role in endothelial identity during development by suppressing RUNX1 through binding to its promoter and directing stem and progenitor cells toward an endothelial rather than a hematopoietic cell fate. RUNX1 functions as a key regulator of myeloid differentiation, aberrant angiogenesis and adverse cardiac remodeling. Previously, we found that RUNX1 inhibition reverses pulmonary hypertension (PH) in multiple animal models. Here, we hypothesize that impaired expression of SOX17 in PAH leads to endothelial cell (EC) dysfunction by failing to suppress RUNX1. METHODSHuman pulmonary artery endothelial cells (HPAECs) with stable SOX17 CRISPR/Cas9 knockout or RUNX1 overexpression were generated and examined for endothelial and hematopoietic gene expression, proliferation, migration, apoptosis, and angiogenesis. Immortalized lymphoblastoid cell lines (LCLs) from PAH patients with SOX17 mutations and healthy controls were reprogrammed into induced pluripotent stem cells (iPSCs) and differentiated into ECs. The effect of RUNX1 inhibition on Sugen/hypoxia-PH was examined in rats, SOX17 enhancer knockout (SOX17enhKO) mice, and Cdh5-CreERT2;Runx1(flox/flox);SOX17enhKO triple transgenic mice. SOX17 and RUNX1 expression were analyzed in peripheral blood samples from PAH patients (n=359). RESULTSHPAECs with SOX17 deletion or RUNX1 overexpression exhibited decreased expression of EC markers, enhanced proliferation and migration, defective angiogenesis, and decreased apoptosis. RUNX1 siRNA knockdown or RUNX1 inhibition by Ro5-3335 partially restored the endothelial properties in SOX17 KO HPAECs. ECs differentiated from SOX17 mutant PAH patient iPSCs exhibited upregulated RUNX1 expression and loss of endothelial identity, which was also partially restored by RUNX1 siRNA or Ro5-3335. In addition, SOX17enhKO mice had increased RUNX1 expression and susceptibility to Sugen/hypoxia-induced PH (SuHx-PH). Treatment with RUNX1 inhibitors or inducible endothelial-specific deletion of RUNX1 rescued SuHx-PH susceptibility in SOX17enhKO mice. RUNX1 inhibitors Ro5-3335 and Ro24-7429 also reversed SuHx-PH in wild-type rats. In addition, plasma RUNX1 expression was higher in PAH patients lacking detectable SOX17 expression than in patients with detectable SOX17 expression. CONCLUSIONSImpaired SOX17 expression increases the risk of PAH through insufficient suppression of RUNX1, leading to pulmonary endothelial dysfunction. RUNX1 inhibition mitigates PH associated with SOX17 deficiency and may represent a novel therapeutic strategy for PAH, especially those with rare or common SOX17 mutations.

cell biology↗

bioRxiv2026

Host tRNA modifications drive efficient translation of influenza A virus genome and impact host antiviral stress responses

Influenza A virus (IAV), as all other viruses, is completely dependent on the host translation machinery components, including host transfer RNAs (tRNAs), to effectively decode its genome. However, while the human genome is biased towards cytosine (C) and guanosine (G)-ending codons, the IAV genome is skewed towards adenine (A) and uridine (U)-ending codons. Nevertheless, translation of IAVs RNA genome is highly efficient. Here we show that host tRNA and tRNA epitranscriptome dynamics are important regulators of IAV RNA translation and host antiviral responses. We show that the levels of several tRNA modifications, including 5-methylcarboxymethyluridine (mcm5U34) and 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U34), and their cognate writers, vary over the course of IAV infection. Additionally, we demonstrate that a set of tRNAs are preferentially recruited to ribosomes upon IAV infection, in line with IAV codon usage requirements. We further show that loss of ELP3, the catalytic subunit of the elongator complex, which is involved in the catalysis of mcm5U34 and of mcm5s2U34, induces tRNA hypomodifications, impairs translation of codon biased IAV genes and triggers the integrated stress response (ISR), interfering with IAV propagation. Taken together, our results uncover the relevance of host tRNAs and their modifications for optimal expression of viral genomes and host antiviral responses, setting the tRNA epitranscriptome as a promising target for the development of host-based antiviral therapies.

molecular biology↗

bioRxiv2026

Orthogonal Transposons for Iterative Genome Engineering of Mammalian Cells.

The contemporary shift toward multispecific antibodies, antibody-drug conjugates (ADCs), and bespoke glycoengineered therapeutics have exposed the limitations of standard genomic engineering tools. This paper presents a novel iterative engineering paradigm utilizing the Leap-In Transposase(R) platform. By leveraging a suite of three mutually orthogonal transposase-transposon systems, we demonstrate the sequential modification of the Chinese Hamster Ovary (CHO) genome to achieve three distinct functional outcomes: (i) First, the creation of a glutamine synthetase (GS)-deficient host (CHO-K1-GS) via targeted knockdown, (ii) Second, the integration of multiple copies of a model therapeutic IgG1 for expression, and (iii) Third, the subsequent knockdown of the fucosylation pathway to modulate the glycan profile of the expressed IgG1. Genetic stability (copy number & sequence) of each integration event was confirmed using Targeted Locus Amplification (TLA) and Next-Generation Sequencing (NGS). Functional stability (expression levels, metabolic phenotype, and glycan phenotypes) was confirmed using standard cell culture and analytical techniques. Crucially, the truly orthogonal nature of the transposase-transposon pairs prevents cross-mobilization and ensures the structural and functional integrity of previously integrated cargo. This study establishes a "What You See Is What You Get" (WYSIWYG) methodology that provides a robust, scalable, and predictable framework for developing next-generation complex biopharmaceutical manufacturing cell lines.

bioengineering↗

bioRxiv2025

The Liver is an Inflammatory Mediator of Pulmonary Arterial Hypertension

The livers contribution to pulmonary arterial hypertension (PAH) pathogenesis remains unclear. We hypothesized that the liver promotes inflammatory injury to the pulmonary endothelium. PAH patients without liver disease with pulmonary artery endothelial cell (PAEC) biopsies were included. Liver serologies and imaging were analyzed by unsupervised classification and regression tree (CART) to identify subclinical liver dysfunction clusters. Two machine-learning models predicted cluster assignment and informed differential expression. PAEC transcriptomes were compared to liver and lung data from monocrotaline and Sugen-Hypoxia rats. Liver fibrosis was assessed in rat and human PAH livers. Among 25 PAH patients (76% female, median age 61 [30 - 84] years), CART identified clusters distinguished by Model for End-Stage Liver Disease Sodium (MELD-Na) [≥]12, predicting higher pulmonary vascular resistance ({beta}=0.5 Wood units per point increase in MELD-Na, 95% CI 0.2-0.8, p=0.005) after adjustment for right atrial pressure. Subjects with MELD-Na [≥]12 had decreased 6-minute walk distance (353 [120 - 576] m vs. 411[300 - 600] m, p=0.03), with upregulation of apelin, beta-catenin, and immune signaling. Rat lung ECs demonstrated survival and hepatic growth-factor signaling, while rat livers showed immune activation. Rat (20.8 vs 16.6 % area stained, p=0.09) and human PAH livers revealed fibrosis despite absent right ventricular failure, supporting a pathogenic lung-liver axis in PAH.

cell biology↗

bioRxiv2025

Allogeneic Polyclonal CD38KO/CD38-CAR γδT Cells For The Treatment Of T Cell Malignancies

Relapsed and refractory T cell malignancies are associated with poor clinical outcomes. Autologous sources of {beta}T cells have been employed for chimeric antigen receptor (CAR) therapies to eliminate the potential for graft-vs-host disease (GvHD). However, the application of CAR-T therapy for T-ALL has been hindered by an inability to obtain sufficient healthy {beta}T cells from patients combined with fratricide due to concurrent antigen expression on normal T cells. Here, we genetically engineered polyclonal {gamma}{delta}T cells, which do not cause GvHD, as an allogeneic source for cancer immunotherapy targeting the pancancer antigen CD38. Utilizing a novel expansion protocol in combination with CRISPR/AAV gene editing, we developed CD38KO/CD38-CAR polyclonal {gamma}{delta}T cells that target T-ALL. Our editing strategy enabled site-directed, on-target insertion of the CD38-CAR transgene into the CD38 locus, with no evidence of significant random CAR DNA integration (as commonly seen with lentiviral CAR transduction) or chromatin abnormalities resulting from CRISPR editing. This enhanced targeting effectively mitigated fratricide through simultaneous CD38 disruption and CAR expression. We demonstrated the efficacy of the CD38KO/CD38-CAR {gamma}{delta}T cells in vitro across multiple patient-derived T-ALL samples collected at baseline and relapse. In vivo, a single injection of CD38KO/CD38-CAR {gamma}{delta}T cells without exogenous cytokine support resulted in potent anti-leukemic efficacy. Fratricide-resistant CD38KO/CD38-CAR polyclonal {gamma}{delta}T cells thus represent a promising off-the-shelf therapeutic platform for T cell malignancies and other CD38-expressing cancers. Key PointsO_LIHybrid pan-{gamma}{delta}TCR antibody/mbIL21-41BBL feeder expansion yields high-purity, polyclonal {gamma}{delta}T cells suitable for CRISPR/AAV editing. C_LIO_LIOn-target CD38-CAR knock-in with simultaneous CD38 knockout prevents fratricide and enables potent T-ALL killing in vitro and in vivo. C_LI

immunology↗

bioRxiv2025

Cell Line Development for Bispecific Antibodies: Better Predictability Through Transposases

Bispecific antibodies are at the forefront of biopharmaceutical drug development. With over 100 different molecular architectures combined with diverse individual subunit sequences, choosing the most suitable structure and predicting the ideal subunit expression ratios for successful heterodimerization is a significant challenge. In this paper, we demonstrate that the recently described cell line development paradigm shift (Rajendran et al. 2021), enabled by the Leap-In transposon platform, can be extended to the development of bispecific monoclonal antibody-producing cell substrates (stable clones and pools). The key features are 1) Parental pools reliably predict the derivative clonal productivity and clonal heterodimer fractions. 2) Clonal productivity and clonal heterodimer fraction remained stable for at least 60 population doublings. 3) Depending on the products biophysicochemical properties, the stable pools exhibit variable productivity stability. 4) Heterodimer fractions remain stable in the Leap-In mediated stable pools independently of the productivity stability of the pools. 5) Structures and subunit ratios can be triaged at stable pool level, and 6) Due to the homogeneous clonal productivity distribution, only a small number ([~]50) of clones need to be isolated and characterized.

bioengineering↗

bioRxiv2025

The Neural Architecture of Dream Recall Frequency: Insights from Interindividual Variations in Brain Structure and Function

Dreaming represents a complex and universal aspect of human sleep, yet it remains an intriguing phenomenon, with the neural mechanisms underlying dream experiences and their frequency not fully understood. This study employs a multimodal neuroimaging approach, integrating quantitative multi-parameter mapping, diffusion tensor imaging, and resting-state functional MRI, to investigate the neural correlates of dream recall frequency (DRF) in a large cohort of 258 healthy individuals. By employing Linked Independent Component Analysis (LICA), we were able to discern distinctive patterns of brain structure and function that correlated with variations in DRF. Our findings elucidate a complex relationship between dream recall and brain microstructure integrity, particularly in white matter regions of the orbitofrontal cortex, parahippocampal gyrus, superior parietal lobule, and occipital cortex. Higher DRF was related to increased white matter microstructure integrity in these regions and decreased gray matter volume in occipital and temporal areas. In terms of functional measures, higher DRF was associated with reduced connectivity across a range of resting-state networks, including the default mode, visual, and dorsal attention networks. This was particularly evident in the right precuneus and posterior cingulate cortex. These results suggest that enhanced dream recall may be related to the organization of higher-order visual and cognitive processing areas, supporting a top-down model of dreaming. This study contributes to a more comprehensive understanding of the neural substrates underlying individual differences in dream recall, offering a foundation for future investigations into the neurobiology and causal relationships of dreaming.

neuroscience↗

bioRxiv2025

Leaky evidence accumulation accounts for perceptual confidence and subjective duration

Perceptual consciousness is defined as the subjective experience associated with the processing of sensory cues from the environment. Subjective experience unfolds over time and is accompanied by a sense of confidence, yet the mechanisms underlying these two properties remain elusive. Here, we propose a computational mechanism that accounts not only for the onset of subjective experience but also its subjective duration and associated feeling of confidence. Our model assumes that a percept becomes conscious when an ongoing, leaky accumulation of sensory evidence surpasses a perceptual threshold and stops being conscious when it falls back below the threshold due to leakage. Crucially, this perceptual threshold can be lower than the decision threshold for reporting the percept. Moreover, our model derives confidence in accurately detecting sensory evidence from the maximum reached by the evidence accumulation process following stimulus onset. We conducted a preregistered study in which three distinct models of evidence accumulation were fitted to behavioral reports of detection, confidence, and subjective duration during a face detection task under temporal uncertainty. The leaky evidence accumulation model accounted for the observed behavioral data best and outperformed alternative models without leakage. In a follow-up experiment, we investigated the impact of leakage adaptation on detection and subjective duration. We found that changes in leakage induced by contextual variations of face duration influenced both detection rates and subjective duration, as predicted by our model. Altogether, our findings suggest that leaky evidence accumulation is a suitable candidate mechanism to explain qualitative aspects of subjective experience, including subjective duration and feelings of confidence.

neuroscience↗

bioRxiv2025

Disruption of ADNP-KDM1A-GTF2I complex drives neural differentiation imbalance in Helsmoortel-Van der Aa syndrome

Mutations in ADNP (Activity-Dependent Neuroprotective Protein) are among the most frequent monogenic causes of autism spectrum disorder (ASD) and lead to Helsmoortel-Van der Aa syndrome (HVDAS). Yet how ADNP dysfunction leads to HVDAS is unclear. We employed patient-derived induced pluripotent stem cells, cortical organoids and ADNP KO human neural stem cells (hNSCs) to clarify the cellular and molecular mechanism of HVDAS onset. We purified an ADNP-KDM1A-GTF2I (AKG) protein complex from hNSCs and show that it targets transposable elements (TEs) to repress nearby gene transcription. Upon ADNP KO, KDM1A binding is lost at promoters targeted by AKG, pointing to ADNP as the anchoring subunit of the AKG complex. HVDAS cortical organoids show impaired progenitor proliferation and accelerated neuronal differentiation, coupled with a sustained upregulation of neurogenesis transcriptional programs, including key transcription factors normally repressed by AKG. This work suggests that the AKG complex acts as the relevant ADNP unit in the molecular onset of HVDAS.

neuroscience↗

bioRxiv2024

Induction of hemodynamic traveling waves by glial-related vasomotion in a rat model of neuroinflammation: implications for functional neuroimaging

BackgroundCerebral hemodynamics are crucial for brain homeostasis and serve as a key proxy for brain activity. Although this process involves coordinated interaction between vessels, neurons and glial cells, its dysregulation in neuroinflammation is not well understood. MethodsWe used in vivo mesoscopic functional ultrasound imaging to monitor cerebral blood volume changes during neuroinflammation in male rats injected with lipopolysaccharide (LPS) in the visual cortex, under resting-state or visual stimulation, combined to advanced ex vivo techniques for glial cell reactivity analysis. FindingsCortical neuroinflammation induced large oscillatory hemodynamic traveling waves in the frequency band of vasomotion ([~]0.1 Hz) in both anesthetized and awake rats. Vasomotor waves traveled through large distances between adjacent penetrating vessels, spanning the entire cortex thickness, and even extending to subcortical areas. Moreover, vasomotion amplitude correlated with microglial morphology changes and was significantly reduced by astrocytic toxins, suggesting that both microglia and astrocytes are involved in the enhancement of vasomotion during neuroinflammation. Notably, functional connectivity was increased under this oscillatory state and functional hyperemia was exacerbated. InterpretationThese findings reveal new spatiotemporal properties of cerebral vasomotion and suggest this is a major component of brain hemodynamics in pathological states. Moreover, reactive microglia and astrocytes are participating to increased vasomotion during neuroinflammation. For the field of functional neuroimaging, our results advocate for considering 0.1 Hz hemodynamic oscillations as an important complement to traditional measurements, particularly in neuroinflammatory conditions. Indeed, brain hemodynamics may provide insights not only into neuronal activity but also glial reactivity. FundingSupported by ANR ("LabCom-NI2D") and Auvergne-Rhone-Alpes Region ("BI2D").

neuroscience↗

bioRxiv2024

Unveiling novel conserved HIV-1 open reading frames encoding T cell antigens using ribosome profiling.

The development of ribosomal profiling (Riboseq) revealed the immense coding capacity of human and viral genomes. Here, we used Riboseq to delineate the first translatome of HIV-1 in infected CD4+ T cells. In addition to canonical viral protein coding sequences (CDSs), we identify 98 alternative open reading frames (ARFs), corresponding to small Open Reading Frames (sORFs) that are distributed across the HIV genome including the UTR regions. Using a database of HIV genomes, we observed that most ARF amino-acid sequences are likely conserved among clade B and C of HIV-1, with 8 ARF-encoded amino-acid sequences being more conserved than the overlapping CDSs. Using T cell-based assays and mass spectrometry-based immunopeptidomics, we demonstrate that ARFs encode viral polypeptides. In the blood of HIV-infected individuals, ARF-derived peptides elicit potent poly-functional T cell responses mediated by both CD4+ and CD8+ T cells. Our discovery expands the list of conserved viral polypeptides that are targets for vaccination strategies and might reveal the existence of viral microproteins or pseudogenes.

immunology↗

bioRxiv2024

Neural correlates of nightmares revisited: findings from large-scale fMRI cohorts

Study ObjectivesNightmares are linked to daytime distress and psychiatric and neurological disorders. However, knowledge about the brain regions involved in nightmare production is sparse. This study aimed to examine the relationship between nightmare frequency and the functional connectivity of the amygdala with the prefrontal cortex, which is central to emotional regulation. Additionally, the study sought to replicate previous findings on the neural correlates of nightmares using two large cohorts. Methods464 participants underwent functional and structural MRI recordings and answered questions assessing nightmare and dream recall frequency. A general linear model assessed the voxelwise correlation between the amygdala-prefrontal cortex connectivity with nightmare frequency. Additionally, regional homogeneity (ReHo) maps were calculated, high and low nightmare frequency and the entire nightmare frequency spectrum contrasts were determined while controlling for age, sex, and dream recall frequency. ResultsThe study did not find a significant correlation between nightmare frequency and amygdala-prefrontal cortex connectivity. Previous ReHo findings of group differences between high and low nightmare frequency could not be replicated. However, parametric analysis revealed an association between nightmare frequency and ReHo differences in the cerebellum. ConclusionsThis failure to confirm hypothesized and previously reported results, especially with a larger sample size, suggests a need to reevaluate the existing knowledge of the neural correlates of nightmares and consider individual differences such as personality, trauma history, and cognitive processes. Overall, our findings highlight the complexities of interpreting neuroimaging data in sleep research.

neuroscience↗

bioRxiv2024

Muscle weakness and mitochondrial stress occur before metastasis in a novel mouse model of ovarian cancer cachexia

ObjectivesA high proportion of women with advanced epithelial ovarian cancer (EOC) experience weakness and cachexia. This relationship is associated with increased morbidity and mortality. EOC is the most lethal gynecological cancer, yet no preclinical cachexia model has demonstrated the combined hallmark features of metastasis, ascites development, muscle loss and weakness in adult immunocompetent mice. MethodsHere, we evaluated a new model of ovarian cancer-induced cachexia with the advantages of inducing cancer in adult immunocompetent C57BL/6J mice through orthotopic injections of EOC cells in the ovarian bursa. We characterized the development of metastasis, ascites, muscle atrophy, muscle weakness, markers of inflammation, and mitochondrial stress in the tibialis anterior (TA) and diaphragm [~]45, [~]75 and [~]90 days after EOC injection. ResultsPrimary ovarian tumour sizes were progressively larger at each time point while robust metastasis, ascites development, and reductions in body, fat and muscle weights occurred by 90 Days. There were no changes in certain inflammatory (TNF), atrogene (MURF1 and Atrogin) or GDF15 markers within both muscles whereas IL-6 was increased at 45 and 90 Day groups in the diaphragm. TA weakness in 45 Day preceded atrophy and metastasis that were observed later (75 and 90 Day, respectively). The diaphragm demonstrated both weakness and atrophy in 45 Day. In both muscles, this pre-metastatic muscle weakness corresponded with considerable reprogramming of gene pathways related to mitochondrial bioenergetics as well as reduced functional measures of mitochondrial pyruvate oxidation and creatine-dependent ADP/ATP cycling as well as increased reactive oxygen species emission (hydrogen peroxide). Remarkably, muscle force per unit mass at 90 days was partially restored in the TA despite the presence of atrophy and metastasis. In contrast, the diaphragm demonstrated progressive weakness. At this advanced stage, mitochondrial pyruvate oxidation in both muscles exceeded control mice suggesting an apparent metabolic super-compensation corresponding with restored indices of creatine-dependent adenylate cycling. ConclusionThis mouse model demonstrates the concurrent development of cachexia and metastasis that occurs in women with EOC. The model provides physiologically relevant advantages of inducing tumour development within the ovarian bursa in immunocompetent adult mice. Moreover, the model reveals that muscle weakness in both TA and diaphragm precedes metastasis while weakness also precedes atrophy in the TA. An underlying mitochondrial bioenergetic stress corresponded with this early weakness. Collectively, these discoveries can direct new research towards the development of therapies that target pre-atrophy and pre-metastatic weakness during EOC in addition to therapies targeting cachexia. HighlightsO_LIThis study reports the first orthotopic model of metastatic ovarian cancer cachexia that can be induced in adult immunocompetent mice C_LIO_LIDiaphragm and limb muscle weakness precedes metastasis and atrophy during ovarian cancer C_LIO_LISkeletal muscle mitochondrial oxidative and redox stress signatures occur during pre-metastatic stages of ovarian cancer C_LIO_LISpecific muscle force as well as mitochondrial pyruvate oxidation and creatine metabolism demonstrate compensation in later stages C_LIO_LIOvarian cancer has heterogeneous effects on distinct muscle types across time C_LI

physiology↗

bioRxiv2024

A functional overlap between evidence accumulation, confidence, and changes of mind in the pre-supplementary motor area and insula

Evidence accumulation models have proven to be powerful tools to explain the temporal dynamics of decisions, as well as their metacognitive components such as confidence judgments and changes of mind. However, it is still unclear how and where in the brain evidence accumulation leads to these two metacognitive components. To better understand the functional overlap between evidence accumulation, confidence, and changes of mind, we recorded intracranial high-gamma activity in patients with focal epilepsy while they reported the motion direction of a random dot kinetogram with a computer mouse, and estimated their confidence level. We found an anatomical overlap between the neural correlates of evidence accumulation, confidence, and changes of mind in the pre-supplementary motor area, as well as in the orbitofrontal, inferior frontal, and insular cortices. Both mouse-tracking behaviour and electrophysiological results were reproduced with a post-decisional evidence accumulation model. After characterising the temporal dynamics of decision-making with mouse-tracking and intracranial electrophysiology, we conclude that confidence and changes of mind result from evidence accumulation instantiated before the decision in the pre-supplementary motor area, and after the decision in the insula.

neuroscience↗

bioRxiv2024

Cortical evidence accumulation for perceptual experience occurs irrespective of reports

Perceptual experience is a multi-faceted, dynamical process, tackled empirically through measures of stimulus detectability and confidence. To assess if stimulus detection and confidence can be explained by evidence accumulation, a form of sequential sampling of sensory evidence, we analyzed high-gamma activity from stereo-electroencephalographic data of 29 participants partaking in 3 pre-registered experiments. In an immediate-response experiment, individual channels and decoded multivariate latent variables in the visual, inferior frontal, and anterior insular cortices displayed functional markers of evidence accumulation. In two further experiments, this signal in the ventral visual cortex differentiated between (1) seen and unseen stimuli in delayed detection, (2) high and low intensity stimuli during passive viewing, and (3) levels of confidence when stimuli were seen. A computational model of leaky evidence accumulation successfully reproduced both behavioral and neural data. Overall, these results indicate that evidence accumulation explains key aspects of perceptual experience, encompassing both conscious access and monitoring.

neuroscience↗