Biology subjects

Domenech, P.

Publications and source records attributed to Domenech, P..

6 recordsLinked to original sources

bioRxiv2025

Recasting adaptation as strategy inference

Flexible adaptation to uncertain and changing environments requires dynamic adjustments in behavioral strategies. While classical learning theories emphasize incremental strengthening of local stimulus-action associations in adaptation, emerging evidence suggests that global-level strategy representations may enable rapid inference of adaptive behaviors, thus promoting efficient decision-making. However, it remains unclear to what extent direct inference over putative strategies can fully account for human adaptation across diverse statistical contexts. Here, we demonstrate clear behavioral markers supporting the broad use of inference over strategies in human adapting to rapid changes. These markers are fully explained solely by a novel model of inference over a structured space of strategies. We further show that inference over strategies is influenced by latent contextual statistics that are beyond the scope of models based on incremental learning. Taken together, these results establish the importance of direct inference over an abstract strategy space for flexible adaptation in humans.

animal behavior and cognition↗

bioRxiv2023

BCG administration promotes the long-term protection afforded by a single-dose intranasal adenovirus-based SARS-CoV-2 vaccine

Despite medical interventions and several approved vaccines, the COVID-19 pandemic is continuing into its third year. Recent publications have explored single-dose intranasal (i.n.) adenovirus-based vaccines as an effective strategy for curbing SARS-CoV-2 in naive animal models. However, the effects of prior immunizations and infections have yet to be considered within these models. Here, we investigate the immunomodulatory effects of Mycobacterium bovis BCG pre-immunization on a subsequent S-protein expressing i.n. Ad vaccination, termed Ad(Spike). We found that Ad(Spike) alone conferred long-term protection from severe SARS-CoV-2 pathology within a mouse model, yet it was unable to limit initial infection 6 months post-vaccination. While i.n. Ad(Spike) retains some protective effect after 6 months, a single administration of BCG-Danish prior to Ad(Spike) vaccination potentiates its ability to control viral replication of the B.1.351 SARS-CoV-2 variant within the respiratory tract. Though BCG-Danish had no effect on the ability of Ad(Spike) to generate and maintain humoral immunity, it promoted the generation of cytotoxic and Th1 responses over suppressive FoxP3+ TREG cells in the lungs of infected mice. These data demonstrate a novel vaccination strategy that may prove useful in limiting future viral pandemics by potentiating the long-term efficacy of next generation mucosal vaccines within the context of the safe and widely distributed BCG vaccine. One sentence summaryBCG enhances anti-SARS-CoV-2 immunity and protection afforded by a novel adenovirus-vectored vaccine.

immunology↗

bioRxiv2021

Experimental confirmation that an uncommon, yet clinically relevant mutation (G878A) in the rrs gene of Mycobacterium tuberculosis confers resistance to streptomycin.

The effective treatment of patients diagnosed with drug resistant tuberculosis (TB) is highly dependent upon the ability to rapidly and accurately determine the antibiotic resistance/ susceptibility profile of the Mycobacterium tuberculosis isolate(s) involved. Thus, as more and more clinical microbiology laboratories advance towards the routine use of DNA sequence-based diagnostics, it is imperative that their predictive functions extend beyond the well-known resistance-conferring mutations, in order to also encompass as many of the lower-frequency mutations as possible. However, in most cases, the fundamental experimental proof that links these uncommon mutations with phenotypic resistance is still lacking. One such example is the G878A polymorphism within the rrs gene encoding the 16s rRNA. We, and others, have identified this mutation within a small number of drug-resistant M. tuberculosis isolates, although prior to this study a consensus regarding exactly which aminoglycoside antibiotic(s) it conferred resistance toward seems not to have been reached. Here we have employed oligo-mediated recombineering to specifically introduce the G878A polymorphism into the rrs gene of M. bovis BCG - a species very closely related to M. tuberculosis - and demonstrate that it confers low-level resistance to streptomycin alone. In our hands, it does not confer cross-resistance towards amikacin, capreomycin, nor kanamycin. We also demonstrate that the rrsG878A mutation exerts a substantial fitness defect in vitro, that may at least in part explain why clinical M. tuberculosis isolates bearing this mutation appear to be quite rare. Overall, this study provides clarity to the resistance phenotype attributable to the rrsG878A mutation and is relevant to the future implementation of genomics-based diagnostics, as well as the clinical management of patients in situations where this particular polymorphism is encountered.

microbiology↗

bioRxiv2021

Decoding activity in Broca's area predicts the occurrence of auditory hallucinations across subjects

BACKGROUNDFunctional magnetic resonance imaging (fMRI) capture aims at detecting auditory-verbal hallucinations (AVHs) from continuously recorded brain activity. Establishing efficient capture methods with low computational cost that easily generalize between patients remains a key objective in precision psychiatry. To address this issue, we developed a novel automatized fMRI-capture procedure for AVHs in schizophrenia patients. METHODSWe used a previously validated, but labor-intensive, personalized fMRI-capture method to train a linear classifier using machine-learning techniques. We benchmarked the performances of this classifier on 2320 AVH periods vs. resting-state periods obtained from schizophrenia patients with frequent symptoms (n=23). We characterized patterns of BOLD activity that were predictive of AVH both within- and between-subjects. Generalizability was assessed with a second independent sample gathering 2000 AVH labels (n=34 schizophrenia patients), while specificity was tested with a nonclinical control sample performing an auditory imagery task (840 labels, n=20). RESULTSOur between-subject classifier achieved high decoding accuracy (area-under-the-curve, AUC = 0.85) and discriminated AVH from rest and verbal imagery. Optimizing the parameters on the first schizophrenia dataset and testing its performance on the second dataset led to a 0.85 out-of-sample AUC (0.88 for the converse test). We showed that AVH detection critically depends on local BOLD activity patterns within Brocas area. CONCLUSIONSOur results demonstrate that it is possible to reliably detect AVH-states from BOLD signals in schizophrenia patients using a multivariate decoder without performing complex regularization procedures. These findings constitute a crucial step toward brain-based treatments for severe drug-resistant hallucinations.

neuroscience↗

bioRxiv2020

Premature commitment to uncertain beliefs during human NMDA receptor hypofunction

In uncertain environments, accurate decision-making requires integrating ambiguous or conflicting signals - a cognitive inference process thought to require n-methyl-d-aspartate (NMDA) synaptic receptors. Here we characterized the causal impact of human NMDA receptor hypofunction on cognitive inference using placebo-controlled infusions of ketamine in a visual cue combination task. Participants tested under ketamine showed elevated uncertainty, together with impaired cognitive inference despite intact visual processing. This behavioral effect of ketamine was associated in patterns of electrical brain activity with degraded and unbalanced coding of presented cues in associative cortex, followed by premature response preparation in motor cortex. Through quantitative simulations, we propose that these cognitive alterations reflect an urge to explain away the elevated uncertainty triggered by ketamine. This compensatory mechanism may cause the emergence of psychotic symptoms observed under chronic NMDA receptor dysfunction, but also forge unusually strong beliefs when confronted with uncertainty in everyday life.

neuroscience↗

bioRxiv2020

Heterologous production of 1-tuberculosinyladenosine in Mycobacterium kansasii models pathoevolution towards the transcellular lifestyle of Mycobacterium tuberculosis.

Mycobacterium kansasii is an environmental non-tuberculous mycobacterium that causes opportunistic tuberculosis-like disease. It is one of the most closely related species to the M. tuberculosis complex. Using M. kansasii as a proxy for the M. kansasii-M. tuberculosis-common ancestor, we asked whether introducing the M. tuberculosis-specific gene pair Rv3377c-Rv3378c into M. kansasii affects the course of experimental infection. Expression of these genes resulted in the production of an adenosine-linked lipid species, known as 1-tuberculosinyladenosine (1-TbAd), but did not alter growth in vitro under standard conditions. Production of 1-TbAd enhanced growth of M. kansasii under acidic conditions through a bacterial cell-intrinsic mechanism independent of controlling pH in the bulk extracellular and intracellular spaces. Production of 1-TbAd led to greater burden of M. kansasii in the lung of C57Bl/6 mice during the first 24 hours after infection and ex vivo infections of alveolar macrophages recapitulated this phenotype within the same time frame. However, in long-term infections, production of 1-TbAd resulted in impaired bacterial survival in both C57Bl/6 mice and Ccr2-/- mice. We have demonstrated that M. kansasii is a valid surrogate of M. tuberculosis to study virulence factors acquired by the latter organism, yet shown the challenge inherent to studying the complex evolution of mycobacterial pathogenicity with isolated gene complementation. IMPORTANCEThis work sheds light on the role of the lipid 1-tuberculosinyladenosine in the evolution of an environmental ancestor to M. tuberculosis. On a larger scale, it reinforces the importance of horizontal gene transfer in bacterial evolution and examines novel models and methods to provide a better understanding of the subtle effects of individual M. tuberculosis-specific virulence factors in infection settings that are relevant to the pathogen.

microbiology↗