Biology subjects

Fernandes, L.

Publications and source records attributed to Fernandes, L..

8 recordsLinked to original sources

bioRxiv2026

Genome variation of Sporothrix schenckii and Sporothrix brasiliensis

Sporotrichosis, a subcutaneous mycosis caused by dimorphic fungi of the Sporothrix genus, has become a major zoonotic epidemic in South America, primarily driven by Sporothrix brasiliensis. To elucidate the genomic basis of its emergence and antifungal adaptation, we analyzed whole-genome sequences from 94 Sporothrix isolates, integrating single-nucleotide polymorphism (SNP), copy number variation (CNV), and genome-wide association (GWAS) analyses. Comparative genomics revealed 610,242 SNPs within S. brasiliensis and 1,474,627 within S. schenckii, confirming a marked disparity in intraspecific diversity. Phylogenomic tree inference resolved six well-supported S. brasiliensis clades with limited internal divergence, reflecting recent population expansion, while S. schenckii displayed deep phylogeographic structure separating North and South American lineages. CNV profiling identified 158 affected genes in S. brasiliensis (60 gains, 98 losses) and 88 in S. schenckii (54 gains, 34 losses), concentrated near sub-telomeric regions. In S. brasiliensis, gains were enriched for kinases and intracellular trafficking functions, whereas losses involved genes related to translation and primary metabolism, suggesting regulatory reinforcement coupled with metabolic streamlining. A GWAS of itraconazole resistance identified 81 SNPs distributed across multiple scaffolds, with many located within genes related with transport, signaling, and redox balance, supporting a polygenic basis for azole response. Together, these results highlight distinct evolutionary strategies of closely related Sporothrix species and delineate the genomic changes associated with the emergence and drug tolerance of S. brasiliensis.

genomics↗

bioRxiv2026

Brain dynamics of attentional, default-mode and limbic networks are disrupted at rest in Post-COVID-19 Syndrome

BackgroundPost-COVID-19 Syndrome (PCS) is characterised by persistent fatigue, cognitive impairments, and affective symptoms, yet its underlying neural mechanisms remain poorly understood. While static neuroimaging studies have identified resting-state connectivity abnormalities in PCS, such approaches fail to capture the brains dynamic functional organisation. This represents a missed opportunity to understand how alterations at the dynamic macroscale interactions give rise to the complex and fluctuating symptom profile of PCS. Cognitive and emotional processes rely on the brains capacity to flexibly reconfigure large-scale networks over time; disruptions in the exploration and transition between brain states may therefore play a central role in PCS pathophysiology. MethodsResting-state fMRI data were acquired from 20 individuals with PCS (mean age = 41.8 years, SD = 9.4) and 20 age- and sex-matched healthy controls (mean age = 40.6 years, SD = 8.1) using a multi-echo sequence. Following denoising with multi-echo independent component analysis, we applied Leading Eigenvector Dynamics Analysis (LEiDA) to identify recurrent patterns of whole-brain phase synchrony. The optimal number of dynamic brain states was determined using the Dunn index. For each state, we quantified probability of occurrence, lifetime, and transition probabilities, and mapped spatial topographies onto canonical functional networks. Group differences were assessed using ANCOVAs controlling for age, sex, and handedness. Exploratory associations with clinical symptoms, cognitive performance, and inflammatory markers were examined using both frequentist and Bayesian approaches. ResultsFive recurrent dynamic brain states were identified. Compared with controls, PCS participants showed reduced probability of occurrence and shorter lifetime of a visual/dorsal attention state, alongside increased probability of a limbic/default mode network (DMN) state. PCS was also characterised by reduced transitions between visual/dorsal attention and frontoparietal-DMN states, and increased transitions from somatomotor/visual states toward the limbic-DMN configuration. Exploratory analyses revealed that greater expression of the limbic-DMN state was negatively associated with global cognitive performance (MoCA) and positively associated with serum IL-1{beta} levels. ConclusionsPCS is associated with a reorganisation of intrinsic brain dynamics, marked by a shift from externally oriented attentional states toward limbic-DMN configurations. This imbalance may reflect reduced cognitive flexibility and increased sensitivity to interoceptive or affective signals. The observed links between dynamic brain-state expression, cognitive impairment, and peripheral inflammation support a systems-level mechanism through which immune signalling may influence neural function in PCS. Dynamic functional connectivity offers a sensitive framework for capturing these alterations and may inform future mechanistic models of post-viral dysfunction and therapeutic targeting. HighlightsO_LIPost-COVID-19 Syndrome (PCS) is linked to altered intrinsic brain dynamics at rest. C_LIO_LIPatients show reduced engagement of visual and attentional brain states. C_LIO_LIIncreased recruitment of limbic-DMN states suggests a shift toward more internally, emotionally charged focussed brain activity. C_LIO_LIBrain-state dynamics are putatively associated with global cognition and IL-1{beta}. C_LIO_LIReduced brain-state flexibility may underlie cognitive and emotional symptoms in PCS. C_LI

neuroscience↗

bioRxiv2025

Specialised super-enhancer networks in stem cells and neurons

Super-enhancers (SEs) are clusters of enhancers with high transcriptional activity that play essential roles in defining cell identity through regulation of nearby genes. SEs preferentially form multiway chromatin interactions with other SEs and highly transcribed regions in embryonic stem cells. However, the properties of the interacting SEs and their specific contributions to complex regulatory interactions in differentiated cell types remain poorly understood. Here, we compare the structural and functional properties of SEs between embryonic stem cells (ESCs) and dopaminergic neurons (DNs) by combining Genome Architecture Mapping (GAM), chromatin accessibility, histone modification, and transcriptome data. Most SEs are cell-type specific and establish extensive pairwise and multiway chromatin interactions with other SEs and genes with cell-type specific expression. SE interactions span megabase genomic distances and frequently connect distant topologically associating domains. By applying network centrality analyses, we detected SEs with different hierarchical importance. Highest network centrality SEs contain binding motifs for cell-type specific transcription factors, and are candidate regulatory hubs. The functional heterogeneity of SEs is also highlighted by their organisation into modular sub-networks that differ in structure and spatial scale between ESCs and DNs, with more specific and strongly connected SE modules in post-mitotic neurons. Our results uncover both the high complexity and specificity of SE-based 3D regulatory networks and provide a resource for prioritizing SEs with potential roles in transcriptional regulation and disease.

genomics↗

bioRxiv2025

Single-cell transcriptomics reveals the impact of sex and age in the healthy human liver

Background & AimsThe liver is a vital organ composed of parenchymal, nonparenchymal, and immune cell populations. Single-cell sequencing approaches now provide the opportunity to understand how sex and age influence gene expression and cellular function across cell types within the liver. MethodsWe analyzed the cellular composition and interactions for the human liver through single-nucleus RNA sequencing (snRNA-seq), incorporating insights from 37 healthy liver samples. The dataset contains cells from female and male donors spanning more than seven decades of life, and analysis was performed to evaluate the impact of sex and age on differential gene expression, pathway enrichment, and predicted ligand-receptor and protein-protein interactions. ResultsExcluding the X and Y chromosomes, we identified 374 genes uniquely enriched in cells of the female liver and 520 genes enriched in cells of the male liver. Differential expression analysis defined unique circuitries enriched within each cell type between females and males and their impact on cell-cell communication and response to external signals, including enrichment of cholesterol/lipid metabolism, transforming growth factor beta (TGF-beta) signaling, and fibronectin (FN1) production in female cells and bone morphogenic protein (BMP) signaling in male cells. With increased age, we observe a greater diversity in gene expression, including enrichment of genes that regulate neuregulin (NGR) signaling at older ages, while genes regulating insulin growth factor (IGF) signaling are enriched at younger ages. Senescence signatures were also identified for each cell type within the liver. ConclusionsThese results define the activities of healthy cell types within the liver across sex and age and provide a foundation for studies to examine how ancestry, geography, and disease states influence liver function within these contexts. Impact and ImplicationsOur study analyzes 37 human liver samples at the single-cell level to understand how sex and age influence gene expression, cell interactions, and response to signals across liver cell types and sub-types. These findings are of particular significance for researchers who need to understand how sex and age may influence the response of individual cell types to injury or treatment of injury. This dataset will also provide a healthy reference for future studies to understand how ancestry, geography, and disease states shape liver biology across age and sex.

cell biology↗

bioRxiv2024

Mechanistic Insights into Dengue Virus Inhibition by a Clinical Trial Compound NITD-688

Dengue, caused by the dengue virus (DENV), presents a significant public health challenge with limited effective treatments. NITD-688 is a potent pan-serotype DENV inhibitor currently in Phase II clinical trials. However, its mechanism of action is not fully understood. Here, we present the molecular details of how NITD-688 inhibits DENV. NITD-688 binds directly to the nonstructural protein 4B (NS4B) with nanomolar affinities across all four DENV serotypes and specifically disrupts the interaction between NS4B and nonstructural protein 3 (NS3) without significantly changing the interactions between NS4B and other viral or host proteins. NS4B mutations that confer resistance to NITD-688 reduce both NITD-688 binding to NS4B and disruption of the NS4B/NS3 interaction. Specifically, NITD-688 blocks the interaction of NS3 with a cytosolic loop within NS4B. This inhibits the formation of new NS4B/NS3 complexes and disrupts pre-existing complexes in vitro and DENV-infected cells, ultimately inhibiting viral replication. Consistent with this mechanism, NITD-688 retains greater potency in cellular assays with delayed treatment compared to JNJ-1802, another NS4B inhibitor that has been studied in Phase II clinical trials. Together, these findings provide critical insights into the mechanism of action of NITD-688, facilitating the development of novel flavivirus NS4B inhibitors and informing future clinical interventions against DENV.

microbiology↗

bioRxiv2023

Exploring associations between the teat apex metagenome and Staphylococcus aureus intramammary infection risk in primiparous cows under organic directives

The primary objective of this study was to identify associations between teat apex microbiome and Staphylococcus aureus intramammary infection (IMI) risk in primiparous cows during the first 5 weeks after calving. We performed a case-control study using shotgun metagenomics of the teat apex and culture-based milk data collected longitudinally from 710 primiparous cows on 5 organic dairy farms. We observed a strong association between S. aureus DNA in the metagenomic teat apex data prior to parturition and the odds of S. aureus IMI after parturition (OR = 38.9, 95% CI: 14.84-102.21). Differential abundance analysis confirmed this association, with cases having a 23.8 higher log fold change (LFC) in abundance of S. aureus in their samples compared to controls. Of the most prevalent microorganisms in controls, those associated with a lower risk of post-calving S. aureus IMI included Microbacterium phage Min 1 (OR = 0.37, 95% CI: 0.25-0.53), Corynebacterium efficiens (OR = 0.53, 95% CI: 0.30-0.94), Kocuria polaris (OR = 0.54, 95% CI: 0.35-0.82), Micrococcus terreus (OR = 0.64, 95% CI: 0.44-0.93) and Dietzia alimentaria (OR = 0.45, 95% CI: 0.26-0.75). Microcin B17 was the most prevalent antibacterial peptide on the teat apex of cases and controls (99.7% in both groups). The predicted abundance of Microcin B17 was also higher in cases compared to controls (LFC 0.26). Cow and farm random effects often explained a large proportion of the observed variability in the teat apex microbiome, suggesting that our results need to be interpreted within the context of the random effects. IMPORTANCEIntramammary infections (IMI) caused by Staphylococcus aureus remain an important problem for the organic dairy industry. The microbiome on the external skin of the teat apex may play a role in mitigating S. aureus IMI risk, in particular the production of antimicrobial peptides (AMPs) by commensal microbes. However, current studies of the teat apex microbiome utilize a 16S approach, which precludes detection of genomics features such as AMPs. Therefore, further research using a shotgun metagenomic approach is needed to understand what role pre-partum teat apex microbiome dynamics play in IMI risk.

ecology↗

bioRxiv2021

Selecting species for restoration in foundational assemblages

O_LIHumans have long sought to restore species, but little attention has been directed at how to best select a subset of foundation species for maintaining rich assemblages that support ecosystems, like coral reefs and rainforests that are increasingly threatened by environmental change. C_LIO_LIWe propose a two-part hedging approach that selects optimized sets of species for restoration. The first part acknowledges that biodiversity supports ecosystem functions and services, and so it takes precaution against loss by ensuring an even spread of phenotypic traits. The second part maximizes species and ecosystem persistence by weighting species based on characteristics that are known to improve ecological persistence--e.g., abundance, species range and tolerance to environmental change. C_LIO_LIUsing existing phenotypic trait and ecological characteristic data for reef building corals, we identified sets of ecologically persistent species by examining marginal returns in occupancy of phenotypic trait space. We compared optimal sets of species with those from the worlds southern-most coral reef which naturally harbors low coral diversity to show these occupy much of the trait space. Comparison with an existing coral restoration program indicated that current corals used for restoration only cover part of the desired trait space and may be improved by including species with different traits. C_LIO_LISynthesis and applications. While there are many possible criteria for selecting species for restoration, the approach proposed here addresses the need to insure against unpredictable losses of ecosystem services by focusing on a wide range of phenotypic traits and ecological characteristics. Furthermore, the flexibility of the approach enables the functional goals of restoration to vary depending on environmental context, stakeholder values, and the spatial and temporal scales at which meaningful impacts can be achieved. C_LI

ecology↗

bioRxiv2020

Sterol-response pathways mediate alkaline survival in diverse fungi

The ability for cells to maintain homeostasis in the presence of extracellular stress is essential for their survival. Stress adaptations are especially important for microbial pathogens to respond to rapidly changing conditions, such as those encountered during the transition from the environment to the infected host. Many fungal pathogens have acquired the ability to quickly adapt to changes in extracellular pH to promote their survival in the various micro-environments encountered during a host infection. For example, the fungal-specific Rim/Pal alkaline response pathway has been well characterized in many fungal pathogens, including Cryptococcus neoformans. However, alternative mechanisms for sensing and responding to host pH have yet to be extensively studied. Recent observations from a genetic screen suggest that the C. neoformans sterol homeostasis pathway is required for growth at elevated pH. This work explores interactions among mechanisms of membrane homeostasis, alkaline pH tolerance, and Rim pathway activation. We find that the sterol homeostasis pathway is necessary for growth in an alkaline environment, and that an elevated pH is sufficient to induce Sre1 activation. This pH-mediated activation of the Sre1 transcription factor is linked to the biosynthesis of ergosterol, but is not dependent on Rim pathway signaling, suggesting that these two pathways are responding to alkaline pH independently. Furthermore, we discover that C. neoformans is more susceptible to membrane-targeting antifungals in alkaline conditions highlighting the impact of micro-environmental pH on the treatment of invasive fungal infections. Together, these findings further connect membrane integrity and composition with the fungal pH response and pathogenesis.

microbiology↗