Biology subjects

Sepulveda, P.

Publications and source records attributed to Sepulveda, P..

7 recordsLinked to original sources

bioRxiv2026

Goals shape human confidence

Confidence guides our decisions: it determines when we commit to a choice, gather more information, or change our minds. Prominent models treat confidence as a readout of the evidence in support of a decision: given the same evidence, a similar confidence level should follow, regardless of what the decision-maker is trying to achieve. Here we show instead that confidence formation is relative to the goals of the decision-maker. Across value-based and perceptual decisions in different sensory modalities, we manipulated the behavioural goal, requiring participants to select the option with either the most or the least evidence. Reversing the goal reversed the relationship between evidence and confidence: biases previously considered fixed features of a confidence computation, such as the positive evidence bias (PEB), followed the goal rather than the stimulus. We developed a new computational model, GOAL (Goal-Oriented Asymmetric Likelihood), in which evidence is weighted according to its relevance for the current goal, and validated it in behavioural and physiological (pupillometry) experiments. Our findings support a new account of metacognition in which confidence is constructed relative to the goals of the decision-maker, prioritising goal-supportive evidence.

neuroscience↗

bioRxiv2024

Dose escalation pre-clinical trial of novel Dok7-AAV in mouse model of DOK7 congenital myasthenia

Congenital myasthenic syndromes (CMS) are a group of inherited disorders characterised by defective neuromuscular transmission and fatigable muscle weakness. Mutations in DOK7, a gene encoding a post-synaptic protein crucial in the formation and stabilisation of the neuromuscular junction (NMJ), rank among the leading three prevalent causes of CMS in diverse populations globally. The majority of DOK7 CMS patients experience varying degrees of disability despite receiving optimised treatment, necessitating the development of improved therapeutic approaches. Here we executed a dose escalation pre-clinical trial using a DOK7-CMS mouse model to assess the efficacy of Amp-101, an innovative AAV gene replacement therapy. Amp-101 is based on AAVrh74 and contains human DOK7 cDNA under the control of a muscle-restricted promoter. We show that at doses 6x1013vg/kg and 1x1014 vg/kg, Amp-101 generated enlarged NMJs and rescued the very severe phenotype of the model. Treated mice became at least as strong as WT littermates and the diaphragm and tibialis anterior muscles displayed robust expression of DOK7. This data suggests that Amp-101 is a promising candidate to move forward to clinic trials.

neuroscience↗

bioRxiv2023

Identification of omega-3 oxylipins in human milk-derived extracellular vesicles with pro-resolutive actions in gastrointestinal inflammation.

Premature infants (PIs) are at risk of suffering necrotizing enterocolitis (NEC), and infants consuming human milk (HM) show a lower incidence than infants receiving formula. The composition of HM has been studied in depth, but the lipid content of HM-derived small extracellular vesicles (HM sEVs) remains unexplored. We isolated HM sEVs from HM samples and analyzed their oxylipin content using liquid chromatography coupled to mass spectrometry, which revealed the presence of anti-inflammatory oxylipins. We then examined the efficacy of a mixture of these oxylipins in combating inflammation and fibrosis, in vitro and and in a murine model of inflammatory bowel disease (IBD). HM-related sEVs contained higher concentrations of oxylipins derived from docosahexaenoic acid, an omega-3 fatty acid. Three anti-inflammatory oxylipins, 14-HDHA, 17-HDHA, and 19,20-DiHDPA ({omega}3 OXLP), demonstrated similar efficacy to HM sEVs in preventing cell injury, inducing re-epithelialization, mitigating fibrosis, and modulating immune responses. Both {omega}3 OXLP and HM sEVs effectively reduced inflammation in IBD-model mice, preventing colon shortening, infiltration of inflammatory cells and tissue fibrosis. Incorporating this unique cocktail of oxylipins into fortified milk formulas might reduce the risk of NEC in PIs and also provide immunological and neurodevelopmental support.

cell biology↗

bioRxiv2021

Cherry-picking information: humans actively sample evidence to support prior beliefs

No one likes to be wrong. Previous research has shown that participants may underweight information incompatible with previous choices, a phenomenon called confirmation bias. In this paper we argue that a similar bias exists in the way information is actively sought. We investigate how choice influences information gathering using a perceptual choice task and find that participants sample more information from a previously chosen alternative. Furthermore, the higher the confidence in the initial choice, the more biased information sampling becomes. As a consequence, when faced with the possibility of revising an earlier decision, participants are more likely to stick with their original choice, even when incorrect. Critically, we show that agency controls this phenomenon. The effect disappears in a fixed sampling condition where presentation of evidence is controlled by the experimenter, suggesting that the way in which confirmatory evidence is acquired critically impacts the decision process. These results suggest active information acquisition plays a critical role in the propagation of strongly held beliefs over time.

neuroscience↗

bioRxiv2020

Value Shapes Abstraction During Learning

The human brain excels at constructing and using abstractions, such as rules, or concepts. Here, in two fMRI experiments, we demonstrate a mechanism of abstraction built upon the valuation of sensory features. Human volunteers learned novel association rules linking simple visual features. Mixture-of-experts reinforcement learning algorithms revealed that, with learning, high-value abstract representations increasingly guided participants behaviour, resulting in better choices and higher subjective confidence. We also found that the brain area computing value signals - the ventromedial prefrontal cortex - prioritized and selected latent task elements during abstraction, both locally and through its connection to the visual cortex. Such coding scheme predicts a causal role for valuation: in a second experiment, we used multivoxel neural reinforcement to test for the causality of feature valuation in the sensory cortex as a mechanism of abstraction. Tagging the neural representation of a tasks feature with rewards evoked abstraction-based decisions. Together, these findings provide a new interpretation of value as a goal-dependent, key factor in forging abstract representations.

neuroscience↗

bioRxiv2020

Visual attention modulates the integration of goal-relevant evidence and not value

When choosing between options, such as food items presented in plain view, people tend to choose the option they spend longer looking at. The prevailing interpretation is that visual attention increases value. However, in previous studies, value was coupled to a behavioural goal, since subjects had to choose the item they preferred. This makes it impossible to discern if visual attention has an effect on value, or, instead, if attention modulates the information most relevant for the goal of the decision-maker. Here we present the results of two independent studies--a perceptual and a value-based task--that allow us to decouple value from goal-relevant information using specific task-framing. Combining psychophysics with computational modelling, we show that, contrary to the current interpretation, attention does not boost value, but instead it modulates goal-relevant information. This work provides a novel and more general mechanism by which attention interacts with choice.

neuroscience↗

bioRxiv2017

Overexpression Of Hypoxia-Inducible Factor 1 Alpha Improves Immunomodulation By Dental Mesenchymal Stem Cells

BackgroundHuman dental mesenchymal stem cells (MSCs) are considered as highly accessible and attractive MSCs for use in regenerative medicine, yet some of their features are not as well characterized as in other MSCs. Hypoxia-preconditioning and hypoxia inducible factor 1 alpha (HIF-1 alpha) overexpression significantly improve MSC therapeutics, but the mechanisms involved are not fully understood. In the present study, we characterize immunomodulatory properties of dental MSCs and determine changes in their ability to modulate adaptive and innate immune populations after HIF-1 alpha overexpression.\n\nMethodsHuman dental MSCs were stably transduced with GFP (MSCs) or GFP-HIF-1 alpha lentivirus vectors (HIF-MSCs). Hypoxic-like metabolic profile was confirmed by mitochondrial and glycolysis stress test. Capacity of HIF-MSCs to modulate T cell activation, dendritic cell differentiation, monocyte migration and polarizations towards macrophages and NK cell lytic activity was assessed by a number of functional assays in co-cultures. Expression of relevant factors were determined by PCR analysis and ELISA.\n\nResultsWhile HIF-1 alpha overexpression did not modify inhibition of T cell activation by MSCs, HIF-MSCs impaired dendritic cell differentiation more efficiently. HIF-MSCs induced also higher attraction of monocytes, which differentiate into suppressor macrophages, and exhibited enhanced resistance to NK cell-mediated lysis, which support the improved therapeutic capacity of HIF-MSCs. HIF-MSCs also displayed a pro-angiogenic profile characterized by increased expression of CXCL12/SDF1 and CCL5/RANTES and complete loss of CXCL10/IP10 transcription.\n\nConclusionsImmunomodulation and expression of trophic factors by dental MSCs make them perfect candidates for cell therapy. Overexpression of HIF-1 alpha enhances these features and increases their resistance to allogenic NK cell lysis and, hence, their potential in vivo lifespan. Our results further support the use of HIF-1 alpha-expressing dental MSCs for cell therapy in tissue injury and immune disorders.

immunology↗