Biology subjects

Costa, M.

Publications and source records attributed to Costa, M..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

SARS-CoV-2 infection leads to Tau pathological signature in neurons

BackgroundThe coronavirus disease 19 (COVID-19) has represented an issue for global health since its outbreak in March 2020. It is now evident that the SARS-CoV-2 infection results in a wide range of long-term neurological symptoms and is worryingly associated with the aggravation of Alzheimers disease. Little is known about the molecular basis of these manifestations. MethodsSeveral SARS-CoV-2 strain variants were used to infect SH-SY5Y neuroblastoma cells and K18-hACE C57BL/6J mice. The Tau phosphorylation profile and aggregation propensity upon infection were investigated using immunoblot and immunofluorescence on cellular extracts, subcellular fractions, and brain tissue. The viral proteins Spike, Nucleocapsid, and Membrane were overexpressed in SH-SY5Y cells and the direct effect on Tau phosphorylation was checked using immunoblot experiments. ResultsUpon infection, Tau is phosphorylated at several pathological epitopes associated with Alzheimers disease and other tauopathies. Moreover, this event increases Taus propensity to form insoluble aggregates and alters its subcellular localization. ConclusionsOur data support the evidence that SARS-CoV-2 infection in the Central Nervous System triggers downstream effects altering Tau function, eventually leading to the impairment of neuronal function.

neuroscience↗

bioRxiv2023

A leaky integrate-and-fire computational model based on the connectome of the entire adult Drosophila brain reveals insights into sensorimotor processing

The forthcoming assembly of the adult Drosophila melanogaster central brain connectome, containing over 125,000 neurons and 50 million synaptic connections, provides a template for examining sensory processing throughout the brain. Here, we create a leaky integrate-and-fire computational model of the entire Drosophila brain, based on neural connectivity and neurotransmitter identity, to study circuit properties of feeding and grooming behaviors. We show that activation of sugar-sensing or water-sensing gustatory neurons in the computational model accurately predicts neurons that respond to tastes and are required for feeding initiation. Computational activation of neurons in the feeding region of the Drosophila brain predicts those that elicit motor neuron firing, a testable hypothesis that we validate by optogenetic activation and behavioral studies. Moreover, computational activation of different classes of gustatory neurons makes accurate predictions of how multiple taste modalities interact, providing circuit-level insight into aversive and appetitive taste processing. Our computational model predicts that the sugar and water pathways form a partially shared appetitive feeding initiation pathway, which our calcium imaging and behavioral experiments confirm. Additionally, we applied this model to mechanosensory circuits and found that computational activation of mechanosensory neurons predicts activation of a small set of neurons comprising the antennal grooming circuit that do not overlap with gustatory circuits, and accurately describes the circuit response upon activation of different mechanosensory subtypes. Our results demonstrate that modeling brain circuits purely from connectivity and predicted neurotransmitter identity generates experimentally testable hypotheses and can accurately describe complete sensorimotor transformations.

neuroscience↗

bioRxiv2023

The purinergic receptor P2X7 and the NLRP3 inflammasome are druggable host factors required for SARS-CoV-2 infection

Purinergic receptors and NOD-like receptor protein 3 (NLRP3) inflammasome regulate inflammation and viral infection, but their effects on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain poorly understood. Here, we report that the purinergic receptor P2X7 and NLRP3 inflammasome are cellular host factors required for SARS-CoV-2 infection. Lung autopsies from patients with severe coronavirus disease 2019 (COVID-19) reveal that NLRP3 expression is increased in host cellular targets of SARS-CoV-2 including alveolar macrophages, type II pneumocytes and syncytia arising from the fusion of infected macrophages, thus suggesting a potential role of NLRP3 and associated signaling pathways to both inflammation and viral replication. In vitro studies demonstrate that NLRP3-dependent inflammasome activation is detected upon macrophage abortive infection. More importantly, a weak activation of NLRP3 inflammasome is also detected during the early steps of SARS-CoV-2 infection of epithelial cells and promotes the viral replication in these cells. Interestingly, the purinergic receptor P2X7, which is known to control NLRP3 inflammasome activation, also favors the replication of D614G and alpha SARS-CoV-2 variants. Altogether, our results reveal an unexpected relationship between the purinergic receptor P2X7, the NLRP3 inflammasome and the permissiveness to SARS-CoV-2 infection that offers novel opportunities for COVID-19 treatment.

microbiology↗

bioRxiv2023

The major-minor mode dichotomy in music perception: A systematic review on its behavioural, physiological, and clinical correlates

Since ancient Greece, major and minor modes in Western tonal music have been identified as the primary responsible musical feature for eliciting emotional states. As such, the underlying correlates of the major-minor mode dichotomy in music perception have been extensively investigated through decades of psychological and neuroscientific research, providing plentiful yet often discordant results. Specifically, crucial questions remain about the several factors contributing to the affective perception of major and minor modes, at times very different among individuals. Moreover, major and minor mode perception has never been quantitatively compared in literature. This comprehensive systematic review and meta-analysis aimed to provide a qualitative and quantitative synthesis of musical mode perception and its behavioural and neural correlates. The qualitative synthesis resulted in 69 studies, showing great diversity in how the major-minor dichotomy has been empirically approached. Most studies reviewed were conducted on adults, considered participants expertise, employed real-life musical stimuli, performed behavioural evaluations, and were carried out among Western listeners. Behavioural, electroencephalography, and neuroimaging meta-analyses (36 studies) consistently showed that major and minor mode elicit distinct neural and emotional responses. Based on our findings, a framework to describe a Major-Minor Mode(l) of music perception and its behavioural and physiological correlates is proposed, incorporating individual factors such as age, expertise, cultural background, and emotional disorders. Limitations, implications, and suggestions for future research are discussed, including putative clinical applications of major-minor dichotomy and best practices regarding stimulation paradigms for musical mode investigation. Public Significance StatementThis study provides qualitative and quantitative evidence of the distinct behavioral and neural responses elicited by major and minor mode, while also highlighting the influence of factors such as age, culture, personality, and health. Results offers a detailed overview of the major-minor dichotomy in music, putting forward an integrated and critical discussion of methodologies, paradigms, and clinical implications of this pivotal musical feature.

neuroscience↗

bioRxiv2023

Age-related brain mechanisms underlying short-term recognition of musical sequences: An EEG study

Recognition is the ability to correctly identify previously learned information. It is an important part of declarative episodic memory and a vital cognitive function, which declines with ageing. Several studies investigated recognition of visual elements, complex images, spatial patterns, and musical melodies, focusing especially on automatic and long-term recognition. Here, we studied the impact of ageing on the event-related potentials using electroencephalography (EEG) associated with short-term recognition of auditory sequences. To this end, we recruited 54 participants, which were divided into two groups: (i) 29 young adults (20-30 years old), (ii) 25 older adults (60-80 years old). We presented two sequences with an interval of a few seconds. Participants were asked to state how similar the second sequence was with regards to the first one. The neural results indicated a stronger negative, widespread activity associated with the recognition of the same sequence compared to the sequences that were transposed or completely different. This difference was widely distributed across the EEG sensors and involved especially temporo-parietal areas of the scalp. Notably, we reported largely reduced neural responses for the older versus young adults, even when no behavioral differences were observed. In conclusion, our study suggests that the combination of auditory sequences, music, and fast-scale neurophysiology may represent a privileged solution to better understand short-term memory and the cognitive decline associated with ageing.

neuroscience↗

bioRxiv2023

Temperature and food chain length, but not latitude, explain region-specific kelp forest responses to an unprecedented heatwave

Kelp forests are among the most abundant coastal marine habitats but are vulnerable to the impacts of climate change. Between 2014 and 2016, an unprecedented heatwave and associated changes in trophic dynamics threatened kelp forests across the Northeast Pacific, with impacts documented from Mexico to Alaska. However, responses have varied substantially and remain poorly characterized across large stretches of coast, especially British Columbia (B.C.), which represents a significant percentage of the range of floating kelp species in the Northeast Pacific. Here, we explore variation in floating kelp (Macrocystis, Nereocystis) persistence pre- and post-heatwave across a >675 km latitudinal gradient, asking whether B.C. kelp forests are of conservation concern. We assembled and analyzed available quantitative kelp data, comparing snapshots of kelp extent before (1994 - 2007) and after (2018 - 2021) the heatwave in 11 regions spanning a range of temperature and sea otter-occupancy statuses, and contextualizing these with time series analyses, where available (n = 7 regions). We provide strong evidence that kelp forests have declined in many regions but with evidence of refugia at both local and regional scales. Kelp forest persistence was negatively correlated with summer sea temperatures in southern B.C., where temperatures varied by ~6{degrees}C across sites, at times exceeding species thermal tolerances. Kelp dynamics in northern regions appeared instead to be modulated by top-down control by urchins and sea otters. Our results demonstrate that B.C.s kelp forest have been substantially reduced in recent years but that regional and local-scale factors influence the resilience of forests to large-scale perturbations.

ecology↗

bioRxiv2023

Chromatin Remodeling Drives Immune-Fibroblast Crosstalk in Heart Failure Pathogenesis

Chronic inflammation and tissue fibrosis are common stress responses that worsen organ function, yet the molecular mechanisms governing their crosstalk are poorly understood. In diseased organs, stress-induced changes in gene expression fuel maladaptive cell state transitions and pathological interaction between diverse cellular compartments. Although chronic fibroblast activation worsens dysfunction of lung, liver, kidney, and heart, and exacerbates many cancers, the stress-sensing mechanisms initiating the transcriptional activation of fibroblasts are not well understood. Here, we show that conditional deletion of the transcription co-activator Brd4 in Cx3cr1-positive myeloid cells ameliorates heart failure and is associated with a dramatic reduction in fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1-positive cells identified a large enhancer proximal to Interleukin-1 beta (Il1b), and a series of CRISPR deletions revealed the precise stress-dependent regulatory element that controlled expression of Il1b in disease. Secreted IL1B functioned non-cell autonomously to activate a p65/RELA-dependent enhancer near the transcription factor MEOX1, resulting in a profibrotic response in human cardiac fibroblasts. In vivo, antibody-mediated IL1B neutralization prevented stress-induced expression of MEOX1, inhibited fibroblast activation, and improved cardiac function in heart failure. The elucidation of BRD4-dependent crosstalk between a specific immune cell subset and fibroblasts through IL1B provides new therapeutic strategies for heart disease and other disorders of chronic inflammation and maladaptive tissue remodeling.

molecular biology↗

bioRxiv2022

Influence of sex-limited mimicry on extinction risk in Aculeata: a theoretical approach.

AO_SCPLOWBSTRACTC_SCPLOWPositive ecological interactions can play a role in community structure and species co-existence. A well-documented case of mutualistic interaction is Mullerian mimicry, the convergence of colour pattern in defended species living in sympatry. By reducing predation pressure, Mullerian mimicry may limit local extinction risks of defended species, but this positive effect can be weakened by undefended mimics (Batesian mimicry). While mimicry was well-studied in neotropical butterflies, it remains surprisingly poorly studied in wasps and bees (Hymenoptera: Aculeata). However, only females are defended in Aculeata and this female-limited defence may modulate the effect of Mullerian mimicry on extinction risks. Here, we focus on the effect of Mullerian mimicry on extinction risk in Aculeata, using a population dynamics model for two species. We show that Mullerian mimicry has a positive effect on species co-existence, but this effect depends on the sex-ratio. We found that the probability of extinction increases as the proportion of undefended males increases in the population, however co-existence still occurs if females are sufficiently abundant or noxious. Furthermore, we detected a destabilising effect of dual sex-limited mimicry (when each sex resembles a different model) on species co-existence. In a context of massive population decline caused by anthropic activities, our findings highlight the potential importance of Mullerian mimicry as an overlooked mechanism linked to extinction risk in wasp and bee species.

ecology↗

bioRxiv2022

Low forces push the maturation of neural precursors into neurons

Mechanical stimulation modulates neural development and neuronal activity. In a previous study, we proposed magnetic "nano-pulling" as a tool to generate active forces. By loading neural cells with magnetic nanoparticles (MNPs), a precise force vector is remotely generated through static magnetic fields. In the present study, human neural stem cells (NSCs) were subjected to a standard differentiation protocol, in the presence or absence of nano-pulling. Under mechanical stimulation, we found an increase in the length of the neural processes which showed an enrichment in microtubules, endoplasmic reticulum, and mitochondria. A stimulation lasting up to 52 days induced a strong remodelling at the level of synapse density and a re-organization of the neuronal network, halving the time required for the maturation of neural precursors into neurons. We then injected the MNP-loaded NSCs into mouse spinal cord slices, demonstrating that nano-pulling stimulates the elongation of the NPC processes and modulates their orientation even in an ex vivo model system. To the best of our knowledge, this is the first evidence showing that active mechanical stimuli can guide the outgrowth of NSCs transplanted into the spinal cord tissue. Our findings suggest that MNPs play an important role in neuronal maturation which could be applied in regenerative medicine.

neuroscience↗

bioRxiv2022

Origin and persistence of polymorphism in loci targeted by disassortative preference: a general model

The emergence and persistence of polymorphism within populations generally requires specific selective regimes. Here, we develop an unifying theoretical framework to explore how disassortative mating can generate and maintain polymorphism at the targeted loci. To this aim, we model the dynamics of alleles at a single locus A in a population of haploid individuals, where reproductive success depends on the combination of alleles carried by the parents at locus A. Our theoretical study of the model confirms that the conditions for the persistence of a given level of allelic polymorphism depend on the relative reproductive advantages among pairs of individuals. Interestingly, equilibria with unbalanced allelic frequencies were shown to emerge from successive introduction of mutants.We then investigate the role of the function linking allelic divergence to reproductive advantage on the evolutionary fate of alleles within population. Our results highlight the significance of the shape of this function on both the number of alleles maintained and their level of genetic divergence. Large number of alleles are maintained with substantial turn-over among alleles when disassortative advantage slowly increases when allelic differentiation becomes large. In contrast, few highly differentiated alleles are predicted to be maintained when genetic differentiation has a strong effect on disassortative advantage. These opposite effects predicted by our model shed light on the levels of allelic differentiation and polymorphism empirically observed in loci targeted by disassortative mate choice.

evolutionary biology↗

bioRxiv2021

ABA represses TOR and root meristem activity through nuclear exit of the SnRK1 kinase

The phytohormone abscisic acid (ABA) promotes plant tolerance to major stresses like drought, partly by modulating plant growth. However, the underlying mechanisms are poorly understood. Here, we show that cell proliferation in the Arabidopsis thaliana root meristem is controlled by the interplay between three kinases, SNF1-RELATED KINASE 2 (SnRK2), the main driver of ABA signaling, the SnRK1 energy sensor, and the growth-promoting TARGET OF RAPAMYCIN (TOR) kinase. Under favorable conditions, the SnRK11 catalytic subunit is enriched in the nuclei of root cells and this is accompanied by normal cell proliferation and meristem size. Depletion of SnRK2s in a snrk2.2 snrk2.3 double mutant causes constitutive cytoplasmic localization of SnRK11 and a reduction in meristem size, suggesting that, under non-stress conditions, SnRK2s enable growth by retaining SnRK11 in the nucleus. In response to elevated ABA levels, SnRK11 translocates to the cytoplasm and this is accompanied by inhibition of TOR, decreased cell proliferation and meristem size. Blocking nuclear export with leptomycin B abrogates ABA-driven SnRK11 relocalization to the cytoplasm and the inhibition of TOR. Fusion of SnRK11 to an SV40 nuclear localization signal leads to defective TOR repression in response to ABA, demonstrating that SnRK11 nuclear exit is a premise for this repression. Altogether, we demonstrate that SnRK2-dependent changes in SnRK11 subcellular localization are crucial for the regulation of TOR activity and root growth in response to ABA. Such swift relocalization of key regulators may represent a more general strategy of sessile organisms like plants to rapidly respond to environmental changes.

plant biology↗

bioRxiv2021

Implications of drift and rapid evolution on negative niche construction

O_LIOrganisms throughout their lives constantly modify their surrounding environment; such activities are often termed niche construction. An important property of niche construction is that its consequences can persist for a long period of time and several subsequent generations can be affected. This phenomenon is described as a time lag in niche construction, or ecological inheritance. C_LIO_LIStudies have suggested that time lag in niche construction can help avoiding the tragedy of the commons. In other words, it can lead to evolution of contribution to a common good, which is associated with positive niche construction, or to the limitation of a common bad, which is associated with negative niche construction. C_LIO_LIIn this article, we will study the evolutionary consequences of incorporating time lags in a negative niche construction process: waste production. We consider a population that extrudes waste into its environment as it consumes resources to grow and reproduce. Higher consumption rates can lead to higher waste production. Individuals that adopt this selfish strategy are expected to be selected as toxic effects are equally shared among all individuals. C_LIO_LIWe show that indeed this tragedy of the commons persists in many cases and selfish strategies evolve in general. When evolution is rapid and intragenerational time lag is incorporated, however, selfish strategies are no longer favoured and strategies resulting in less waste production can be selected. Importantly, heavy pollution results in smaller population sizes, so that drift becomes more important than natural selection and limits the evolution of higher waste production. C_LI

evolutionary biology↗

bioRxiv2021

Dissociation of early and late face-related processes in Autism Spectrum Disorder and Williams syndrome

Williams syndrome (WS) and Autism Spectrum Disorders (ASD) are psychiatric conditions associated with atypical but opposite face-to-face interactions patterns: WS patients overly stare at others, ASD individuals escape eye contact. Whether these behaviors result from dissociable visual processes within the occipito-temporal pathways is unknown. Using high-density electroencephalography, multivariate signal processing algorithms and a protocol designed to identify and extract evoked activities sensitive to facial cues, we investigated how WS (N=14), ASD (N=14) and neurotypical subjects (N=14) decode the information content of a face stimulus. We found two neural components in neurotypical participants, both strongest when the eye region was projected onto the subjects fovea, simulating a direct eye contact situation, and weakest over more distant regions, reaching a minimum when the focused region was outside the stimulus face. The first component peaks at 170ms, an early signal known to be implicated in low-level face features. The second is identified later, 260ms post-stimulus onset and is implicated in decoding salient face social cues. Remarkably, both components were found distinctly impaired and preserved in WS and ASD. In WS, we could weakly decode the 170ms signal based on our regressor relative to facial features, probably due to their relatively poor ability to process faces morphology, while the late 260ms component was highly significant. The reverse pattern was observed in ASD participants who showed neurotypical like early 170ms evoked activity but impaired late evoked 260ms signal. Our study reveals a dissociation between WS and ASD patients and point at different neural origins for their social impairments.

neuroscience↗

bioRxiv2021

A spatial multi-scale fluorescence microscopy toolbox discloses entry checkpoints of SARS-CoV-2 variants in VeroE6 cells

We exploited a multi-scale microscopy imaging toolbox to address some major issues related to SARS-CoV-2 interactions with host cells. Our approach harnesses both conventional and super-resolution fluorescence microscopy and easily matches the spatial scale of single-virus/cell checkpoints. We deployed this toolbox to characterize subtle issues related to the entry phase of SARS-CoV-2 variants in Vero E6 cells. Our results suggest that in these cells the variant of concern B.1.1.7, (aka Alpha variant), became the predominant circulating variant in several countries by a clear transmission advantage. In fact, in these cells B.1.1.7 outcompetes its ancestor B.1.177 in terms of a much faster kinetics of entry. Given the cell-entry scenario dominated by the endosomal "late pathway", the faster internalization of B.1.1.7 could be directly related to the N501Y mutation in the S protein, which is known to strengthen the binding of Spike receptor binding domain with ACE2. Remarkably, we also directly observed the main role of clathrin as mediator of late-entry endocytosis, reconciling it with the membrane localization of the ACE2 receptor previously attributed to caveolin-enriched rafts. Overall, we believe that our fluorescence microscopy-based approach represents a fertile strategy to investigate the molecular features of SARS-CoV-2 interactions with cells.

biophysics↗

bioRxiv2021

Direct tissue sensing reprograms TLR4+ Tfh-like cells inflammatory profile in the joints of rheumatoid arthritis patients

CD4+ T cells mediate rheumatoid arthritis (RA) pathogenesis through both antibody-dependent and independent mechanisms. It remains unclear how synovial microenvironment impinges on CD4+ T cells pathogenic functions. Here, we identified a TLR4+ follicular helper T (Tfh) cell-like population present in the blood and expanded in synovial fluid. Mechanistically, we unveiled that homotypic T-T cell interactions through non-cognate HLA-DR:TCR contacts regulate TLR4 expression on T cells. TLR4+ T cells possess a two-pronged pathogenic activity. Upon TCR and ICOS engagement, TLR4+ T cells produce IL-21, a cytokine known to sponsor antibody production. However, direct TLR4+ engagement on T cells, by endogenous ligands in the arthritic joint, reprograms them towards an IL-17 inflammatory profile compatible with tissue damage program. Blocking TLR4 signaling with a specific inhibitor impaired IL-17 production in response to synovial fluid recognition. Ex vivo, synovial fluid TLR4+ T cells produced IL-17, but not IL-21. TLR4+ T cells appear to uniquely reconcile an ability to promote systemic antibody production with a local synovial driven tissue damage program. TLR4+ T cells could constitute an attractive cellular target and predictive biomarker for erosive arthritis.

immunology↗

bioRxiv2020

League of Brazilian Bioinformatics: a competition framework to promote scientific training

Backgroundthe scientific training to become a bioinformatician includes multidisciplinary abilities, which increase the challenges to professional development. Competition frameworkin order to improve and promote the ongoing training of the Brazilian bioinformatics community, we organize a national competition, with the main goal to develop human resources and abilities in Computational Biology at the national level. The competition framework was designed in three phases: 1) a one-day challenge composed of 60 multiple-choice questions covering Biology, Computer Science, and Bioinformatics knowledge; 2) five Computational Biology challenges to be solved in three days; and 3) development of an original project evaluated during the 15th X-meeting. Resultsthe first edition of the League of Brazilian Bioinformatics (LBB) counted 168 competitors and 59 groups, distributed into undergraduate students (14.4%), graduate students (12.6% master and 16.8%, Ph.D.), and other professional fields. The first phase selected 46 teams to proceed in the competition, while the second phase selected the three top-performing teams. Conclusionduring the competition, we were able to stimulate teamwork in the main areas of Bioinformatics, with the engagement of all research-level competitors. Furthermore, we identified opportunities to deliver and offer better training to the community and we intend to apply the acquired experience in the second edition of the LBB, which will occur in 2021. Supplementary informationSupplementary data are available at Bioinformatics

scientific communication and education↗

bioRxiv2020

Information flow, cell types and stereotypy in a full olfactory connectome

The hemibrain connectome provides large scale connectivity and morphology information for the majority of the central brain of Drosophila melanogaster. Using this data set, we provide a complete description of the Drosophila olfactory system, covering all first, second and lateral horn-associated third-order neurons. We develop a generally applicable strategy to extract information flow and layered organisation from connectome graphs, mapping olfactory input to descending interneurons. This identifies a range of motifs including highly lateralised circuits in the antennal lobe and patterns of convergence downstream of the mushroom body and lateral horn. Leveraging a second data set we provide a first quantitative assessment of inter - versus intra-individual stereotypy. Comparing neurons across two brains (three hemispheres) reveals striking similarity in neuronal morphology across brains. Connectivity correlates with morphology and neurons of the same morphological type show similar connection variability within the same brain as across two brains.

neuroscience↗

bioRxiv2020

The connectome of the adult Drosophila mushroom body: implications for function

Making inferences about the computations performed by neuronal circuits from synapse-level connectivity maps is an emerging opportunity in neuroscience. The mushroom body (MB) is well positioned for developing and testing such an approach due to its conserved neuronal architecture, recently completed dense connectome, and extensive prior experimental studies of its roles in learning, memory and activity regulation. Here we identify new components of the MB circuit in Drosophila, including extensive visual input and MB output neurons (MBONs) with direct connections to descending neurons. We find unexpected structure in sensory inputs, in the transfer of information about different sensory modalities to MBONs, and in the modulation of that transfer by dopaminergic neurons (DANs). We provide insights into the circuitry used to integrate MB outputs, connectivity between the MB and the central complex and inputs to DANs, including feedback from MBONs. Our results provide a foundation for further theoretical and experimental work.

neuroscience↗