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Cunha, F.

Publications and source records attributed to Cunha, F..

10 recordsLinked to original sources

Social inequity aversion and fairness preference in polar bears

Decision-making is key to survival, with choices and behaviour typically shaped by evolutionary pressures to enhance fitness and minimize loss. Inequity aversion, the tendency to respond negatively to unequal reward distributions, is therefore unexpected, as acts of fairness may be costly to the individual in the short term. In social, cooperative species, however, fairness may enhance long-term benefits through stable social interactions. Inequity aversion is believed to promote cooperative social structures and has only been demonstrated in certain social species. Yet, solitary species have not been tested, and whether this behaviour depends on social cooperative structures is unknown. Examining solitary species could clarify whether inequity aversion reflects an adaptation to cooperation or a general cognitive capacity linked to social comparison and reward evaluation. We studied inequity aversion in polar bears (Ursus maritimus), a largely solitary species, using three complementary, non-invasive cognition tests on seven bears from two zoos in the Netherlands. (1) An impunity experiment assessing effort-based inequity, in which bears performed a standardized action to obtain food rewards. (2) A choice-based experiment testing active selection between equal and unequal reward distributions. (3) A no-task control experiment assessing responses to unequal reward distribution without effort. Under effort-based inequity, bears reduced task performance and increased task latency when a partner received a superior reward. Unequal reward distributions did not affect reward acceptance independent of effort. In the choice-based paradigm, bears preferentially selected equal reward distributions with a partner present. Although generalizability to wild populations is limited, these findings demonstrate behavioural aversion of social inequity in a non-cooperative species. Inequality aversion may therefore not be restricted to social, cooperative animals but instead reflect a broadly distributed cognitive mechanism that emerges under relevant social conditions. These findings challenge current theories and advance our understanding of the cognitive foundations of fairness-related behaviour in animals.

animal behavior and cognition↗

Trade-off between foraging and vigilance in the Red-legged Seriema

As foraging increases exposure to predators, individuals must allocate time to vigilance in addition to food acquisition. Although those behaviors are assumed to be mutually exclusive, this is often hard to disentangle, given that multiple sensory modalities are often applied. However, when foraging, animals often have one sensory modality more impaired (e.g. vision), than others (e.g. auditory); thus, a level of compromise on vigilance capabilities is assumed while foraging. Here, we test the idea that when a food item requires manipulation, thus reducing vigilance capabilities, social foraging should promote shared costs of vigilance. We conducted video recordings to investigate whether there is a trade-off between foraging and vigilance behavior in red-legged seriemas (Cariama cristata) when foraging in pairs. We studied the social foraging behavioral patterns while seriemas were feeding on macauba palm (Acrocomia aculeata) fruit, which requires a series of throwing maneuvers to crack the hard outer shell. Our results showed that within a pair recording one individual was observed to spend more time vigilant than their partner, while the other individual spent more time throwing fruit than their partner. However, we found no evidence for synchronization or coordination of vigilance and foraging between individuals within a feeding bout. These results provide insight into the foraging ecology of red-legged seriemas and the trade-off between foraging and vigilance in social contexts.

animal behavior and cognition↗

Nav1.5 expressed in TrkB+ sensory neurons mediates paclitaxel-induced mechanical pain hypersensitivity

Chemotherapy-induced neuropathic pain (CINP) is a frequent and debilitating adverse effect of anti-tumor therapies, for which current treatments are largely non-specific and offer limited efficacy. Identifying molecular mechanisms that drive CINP may enable the development of targeted therapeutic strategies. Here, we demonstrate that paclitaxel-induced mechanical pain hypersensitivity in mice occurs independently of classical Nav1.8+ nociceptors but critically depends on TrkB+ sensory neurons. Transcriptomic analysis of TrkB+ sensory neurons revealed selective expression of Scn5a, which encodes the voltage-gated sodium channel Nav1.5, a channel classically associated with cardiac excitability. Importantly, SCN5A expression was also detected in human primary sensory neurons, indicating potential translational relevance. Functional studies further showed that Scn5a knockdown, using small interfering RNA, significantly attenuates paclitaxel-induced mechanical pain hypersensitivity. Together, these findings identify TrkB+ sensory neurons as key drivers of CINP and reveal Nav1.5 as a previously unrecognized contributor to chemotherapy-induced neuropathic pain. Targeting Nav1.5 in TrkB+ sensory neurons may therefore represent a novel therapeutic strategy for the treatment of CINP.

neuroscience↗

Avian telencephalon and cerebellum volumes can be accurately estimated from digital brain endocasts

For studies of the evolution of vertebrate brain anatomy and potentially associated behaviours, reconstructions of digital brain endocasts from computed tomography scans have revolutionised our capacity to collect neuroanatomical data. However, measurements from digital endocasts must be validated as reflecting actual brain anatomy, which is difficult because the collection of soft tissue information through histology is laborious and time consuming. In birds, the reliability of digital endocast measurements as volume proxies for the two largest brain regions - the telencephalon and cerebellum - remains to be validated despite their use as proxies e.g. of cognitive performance or flight ability. We here use the largest dataset of histology and digital endocasts to date, including 136 species from 25 avian orders, to compare digital endocast surface area measurements with actual brain volumes of the telencephalon, cerebellum, and whole-brain endocast. Using linear and phylogenetically informed regression analyses, we demonstrate that endocast surfaces are strongly correlated with their brain volume counterparts for both absolute and relative size. This provides empirical support for using endocast-derived cerebellar and telencephalic surface areas in existing and future studies of living and extinct birds, with potential to expand to the dinosaur-bird transition in the future.

animal behavior and cognition↗

Pangenomic analysis of Helcococcus ovis reveals widespread tetracycline resistance and a novel bacterial species, Helcococcus bovis.

Helcococcus ovis (H. ovis) is an opportunistic bacterial pathogen of a wide range of animal hosts including domestic ruminants, swine, avians, and humans. In this study, we sequenced the genomes of 35 Helcococcus sp. clinical isolates from the uterus of dairy cows and explored their antimicrobial resistance and biochemical phenotypes. Phylogenetic and average nucleotide identity analyses placed four Helcococcus isolates within a cryptic clade-representing an undescribed species, for which we propose the name Helcococcus bovis sp. nov. We applied whole genome comparative analyses to explore the pangenome, resistome, virulome, and taxonomic diversity of the remaining 31 H. ovis isolates. H. ovis was more often isolated from cows with metritis, however, there was no associations between H. ovis gene clusters and uterine infection. The phylogenetic distribution of high-virulence determinants of H. ovis is consistent with convergent gene loss in the species. The majority of H. ovis strains (30/31) contain mobile tetracycline resistance genes, leading to higher minimum inhibitory concentrations of tetracyclines in vitro. In summary, this study showed that the presence of H. ovis is associated with uterine infection in dairy cows, that mobile genetic element-mediated tetracycline resistance is widespread in H. ovis, and that there is evidence of co-occurring virulence factors across clades suggesting convergent gene loss in the species. Finally, we introduced a novel Helcococcus species closely related to H. ovis, called H. bovis sp. nov. HighlightsO_LIThe presence of Helcococcus ovis is associated with uterine infection in dairy cows C_LIO_LIMobile genetic element-mediated tetracycline resistance is widespread in H. ovis C_LIO_LICo-occurring virulence factors across clades suggest convergent gene loss in the species C_LIO_LIHelcococcus bovis is a novel species closely related to Helcococcus ovis C_LI

microbiology↗

Targeting C5aR1 signaling reduced neutrophil extracellular traps and ameliorates COVID-19 pathology

Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions, and plays immunopathological roles in inflammatory diseases, we investigated whether C5a/C5aR1 pathway could be involved in COVID-19 pathophysiology. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of critically ill COVID-19 patients compared to patients with influenza infection, as well as in the lung tissue of K18-hACE2 Tg mice (Tg mice) infected with SARS-CoV-2. Genetic and pharmacological inhibition of C5aR1 signaling ameliorated lung immunopathology in Tg-infected mice. Mechanistically, we found that C5aR1 signaling drives neutrophil extracellular trap (NET)s-dependent immunopathology. These data confirm the immunopathological role of C5a/C5aR1 signaling in COVID-19 and indicate that antagonist of C5aR1 could be useful for COVID-19 treatment.

immunology↗

Complement receptor C5aR1 signaling in sensory neuron-associated macrophages drives neuropathic pain

Neuroimmune interactions across the pain pathway play a predominant role in the development of neuropathic pain. Previous reports demonstrated that complement driven effector systems including the C5a/C5aR1 axis contribute to these neuro-immune mechanisms. However, the cellular and molecular mechanisms underlying C5a/C5aR1 signaling-mediated neuropathic pain development remain ill-identified. Here we show that neuropathic pain following peripheral nerve injury was attenuated in C5aR1-deficient male and female mice as well as in wild type mice treated with a selective allosteric C5aR1 antagonist. Using two complementary cell-specific C5aR1 knockout mouse strains, we identified C5a/C5aR1 driven-activation of sensory neuron-associated macrophages (sNAMs) located in the sensory ganglia as the key site of peripheral nerve injury-induced neuropathic pain, whereas activation of macrophages of the local of peripheral nerve injury was not involved. Mechanistically, we uncovered IL-1b the main mediator of pain hypersensitivity in response to C5aR1 signaling in sNAMs. Our findings highlight a crucial role of C5a/C5aR1 axis activation in sNAMs for the development of neuropathic pain and identify this pathway as a promising novel target for neuropathic pain therapy.

pharmacology and toxicology↗

Vandetanib Reduces Inflammatory Cytokines and Ameliorates COVID-19 in Infected Mice

The portfolio of SARS-CoV-2 small molecule drugs is currently limited to a handful that are either approved (remdesivir), emergency approved (dexamethasone, baricitinib) or in advanced clinical trials. We have tested 45 FDA-approved kinase inhibitors in vitro against murine hepatitis virus (MHV) as a model of SARS-CoV-2 replication and identified 12 showing inhibition in the delayed brain tumor (DBT) cell line. Vandetanib, which targets the vascular endothelial growth factor receptor (VEGFR), the epidermal growth factor receptor (EGFR), and the RET-tyrosine kinase showed the most promising results on inhibition versus toxic effect on SARS-CoV-2-infected Caco-2 and A549-hACE2 cells (IC50 0.79 M) while also showing a reduction of > 3 log TCID50/mL for HCoV-229E. The in vivo efficacy of vandetanib was assessed in a mouse model of SARS-CoV-2 infection and statistically significantly reduced the levels of IL-6, IL-10, TNF-, and mitigated inflammatory cell infiltrates in the lungs of infected animals but did not reduce viral load. Vandetanib rescued the decreased IFN-1{beta} caused by SARS-CoV-2 infection in mice to levels similar to that in uninfected animals. Our results indicate that the FDA-approved vandetanib is a potential therapeutic candidate for COVID-19 positioned for follow up in clinical trials either alone or in combination with other drugs to address the cytokine storm associated with this viral infection.

immunology↗

Pyronaridine Protects Against SARS-CoV-2 in Mouse

There are currently relatively few small-molecule antiviral drugs that are either approved or emergency approved for use against SARS-CoV-2. One of these is remdesivir, which was originally repurposed from its use against Ebola and functions by causing early RNA chain termination. We used this as justification to evaluate three molecules we had previously identified computationally with antiviral activity against Ebola and Marburg. Out of these we previously identified pyronaridine, which inhibited the SARS-CoV-2 replication in A549-ACE2 cells. Herein, the in vivo efficacy of pyronaridine has now been assessed in a K18-hACE transgenic mouse model of COVID-19. Pyronaridine treatment demonstrated a statistically significant reduction of viral load in the lungs of SARS CoV-2 infected mice. Furthermore, the pyronaridine treated group reduced lung pathology, which was also associated with significant reduction in the levels of pro-inflammatory cytokines/chemokine and cell infiltration. Notably, pyronaridine inhibited the viral PLpro activity in vitro (IC50 of 1.8 {micro}M) without any effect on Mpro, indicating a possible molecular mechanism involved in its ability to inhibit SARS-CoV-2 replication. Interestingly, pyronaridine also selectively inhibits the host kinase CAMK1 (IC50 of 2.4 {micro}M). We have also generated several pyronaridine analogs to assist in understanding the structure activity relationship for PLpro inhibition. Our results indicate that pyronaridine is a potential therapeutic candidate for COVID-19. One sentence summaryThere is currently intense interest in discovering small molecules with direct antiviral activity against the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). Pyronaridine, an antiviral drug with in vitro activity against Ebola, Marburg and SARS-CoV-2 has now statistically significantly reduced the viral load in mice along with IL-6, TNF-, and IFN-{beta} ultimately demonstrating a protective effect against lung damage by infection to provide a new potential treatment for testing clinically.

pharmacology and toxicology↗

Oral microbial dysbiosis linked to worsened periodontal condition in rheumatoid arthritis patients

Rheumatoid arthritis (RA) is an autoimmune disorder associated with increased periodontal destruction. It is thought that RA increases the risk of periodontal disease; it is not known how it influences the oral microbiota. Our aim was to analyze the impact of RA on subgingival microbiota and its association with periodontal inflammation and RA activity. Forty-two patients with RA were compared to 47 control subjects without RA. Patients were screened for probing depth, clinical attachment level, bleeding on probing and classified as with or without periodontitis. Subgingival plaque was examined by Illumina MiSeq Sequencing of 16S rRNA gene V4 region and inflammatory cytokines were measured in saliva. RA was associated to severe periodontal disease. In addition, the severity of RA, reflected by the number of tender and swollen joints, was significantly correlated with the presence of pathogenic oral bacteria (i.e. Fusobacterium nucleatum and Treponema socransky). Non-periodontitis RA patients compared to healthy controls had increased microbial diversity and bacterial load, higher levels of pathogenic species (Prevotella, Selenomonas, Anaeroglobus geminatus, Parvimonas micra, Aggregatibacter actinomycetemcomitans) and reduction of health-related species (Streptococcus, Rothia aeria, Kingela oralis). Genes involved with bacterial virulence (i.e. lipopolysaccharide biosynthesis, peptidases) were more prevalent in the subgingival metagenome of subjects with RA. In addition, the degree of oral inflammation reflected by IL-2, IL-6, TNF-, IFN-{gamma} salivary levels was increased in non-periodontitis RA patients in comparison with controls. Our findings support the hypothesis that RA triggers dysbiosis of subgingival microbiota, which may contribute to worsening periodontal status.\n\nAuthor SummaryRheumatoid arthritis (RA) is an autoimmune disease characterized by joints inflammation, swelling, pain and stiffness. Exactly what starts this disease is still unclear. Some recent studies have suggested mucosal surfaces in the body, like those in the gums, could affect the disease process. It has been observed that people with RA have higher risk of periodontitis (a bacterial inflammatory disease of the gums), compared with the general population, and this may be the start of the autoimmune process. Also, periodontitis increases the severity of RA while interventions by treating periodontitis can improve the symptoms of RA. One of the possible mechanisms that link the higher prevalence of periodontitis in RA patients is the dysbiosis of the oral microbiota triggered by the chronic inflammation in RA. Increased levels of molecules of inflammation may affect the oral environment and change the type of bacteria that live there. Here, we examined RA patients and healthy subjects, screening their oral health and inflammatory markers. We collected their saliva and the dental plaque from the space between the teeth and the gum. We found that RA patients exhibited severe periodontitis, increased levels of inflammatory mediators on their saliva and distinct bacterial communities, with higher proportions of bacteria species linked to periodontal disease, even in patients without periodontitis. We also found that the presence of these bacteria species was linked to worse RA conditions. Our study provides new insights to understand the bi-directional mechanisms linking periodontal disease to the development of RA, showing that we need to pay attention to the oral cavity in patients with RA and refer people for dental evaluation. This practice might have a positive impact in the course of RA.

microbiology↗