Biology subjects

Alvarez, F.

Publications and source records attributed to Alvarez, F..

15 recordsLinked to original sources

bioRxiv2026

AntiSite: Modality Dropout Enables Antibody Paratope Prediction With or Without Structure From a Single Model

Summary: Reliable paratope identification is central to understanding antibody antigen recognition and advancing therapeutic antibody discovery. AntiSite is a unified antibody paratope prediction framework that combines protein language-model sequence embeddings with structure-derived molecular-surface features and, through modality dropout, trains a single checkpoint to predict both with and without a structure. This lets one model support sequence-only inference when no structure is available and structure-aware inference when an antibody structure is provided. Availability and implementation: Source code, trained models and evaluation scripts are freely available at https://github.com/aggelos-michael-papadopoulos/AntiSite. Processed benchmark structures and corrected split metadata are archived on Zenodo at https://doi.org/10.5281/zenodo.21705412.

bioinformatics↗

bioRxiv2026

Oncogene-driven metabolic regulation of Dihydroceramide Desaturase 1 (DES1) converges on GAPDH in matrix-detached conditions

Deregulation of sphingolipid (SL) metabolism is well-established across many cancers, yet the underlying mechanisms that drive changes in SLs are poorly understood. We previously identified dihydroceramide desaturase 1 (DES1) as a downstream target of HER2 and implicated DES1 as a driver of anchorage-independent survival in breast cancer. In this study, we expand on these results to establish the oncogenic PI3K pathway as a driver of post-translational DES1 activity following cell detachment from the extracellular matrix. PI3K activation of DES1 required glucose uptake and metabolism through both glycolysis and the pentose phosphate pathway. However, it did not require glucose flux into the TCA cycle and was independent of antioxidant capacity of the cell. Moreover, Instead, results identify GAPDH - a point of convergence between glycolysis and PPP - as important for oncogene-driven DES1 activity. Overall, this study defines a novel pathway of DES1 regulation and establishes DES1 as a point of crosstalk between glucose and SL metabolic pathways.

Cancer Biology↗

bioRxiv2025

An integrated biobehavioral study of empathy

Empathy, a crucial prosocial human trait, is mainly measured through questionnaires, but performance in tasks involving emotional stimuli, brain activity during these tasks, and genetic information also provide relevant clues. These approaches are developed separately or by combining only some of these factors. Integrating them into a single study and analysis may help to better characterize their relative load and to understand the complexity of empathy. The IRI empathy scale was administered to 65 participants, who later performed a lexical decision task on emotional words while their performance and event-related potentials (ERPs) were recorded. Three genetic polymorphisms, one in the OXTR gene (SNP rs2254298) and two in the AVPR1a gene (RS1 and RS3 regions), were also analyzed. Generalized linear models revealed that these biobehavioral factors jointly predicted emotional but not cognitive empathy. Reaction times and the amplitude of the LPP component of ERPs in response to emotional words, along with rs2254298 AA/AG genotype, were significantly associated with scores on the IRI personal distress subscale. Meanwhile, LPP amplitudes and AVPR1a-RS1 LL genotype significantly predicted scores on the empathy concern subscale. The balanced loading of all these factors in the models reinforces the desirability of a comprehensive, multifaceted approach to characterizing empathy.

neuroscience↗

bioRxiv2025

INFLUENCE OF PREMENSTRUAL SYNDROME ON ATTENTIONAL CAPTURE BY EXPRESSIONS IN THE LUTEAL PHASE

Research on female health has increased thanks to the growing interest in womens well-being. Premenstrual Syndrome (PMS) is characterized by its high incidence and negative emotional symptoms during the luteal phase. While various studies suggest that the menstrual cycle affects emotional processing, the role of PMS has barely been investigated. Prior evidence suggests that the menstrual cycle does not modulate the attentional capture by emotional faces (Alvarez et al., 2022). This study aims to explore PMSs impact on this phenomenon. Forty-seven women performed an attentional capture task in both phases of the menstrual cycle, with emotional faces as distractors. Both behavioral performance and Event-Related Potentials (ERPs) were recorded. Additionally, premenstrual symptoms were monitored over two menstrual cycles. Results showed no significant interaction effect of PMS, either at the behavioral or ERP levels. However, emotional stimuli, particularly angry faces, consistently captured attention more than neutral ones, as reflected in enhanced P1 and N170 components. These results indicate no evidence that PMS modulates exogenous attention to emotional stimuli. Future studies should consider individual affective states, such as depressive and anxiety symptoms associated with PMS, rather than PMS as a category, to further investigate the potential effects of PMS on attentional capture.

neuroscience↗

bioRxiv2024

ParaSurf: A Surface-Based Deep Learning Approach for Paratope-Antigen Interaction Prediction

MotivationIdentifying antibody binding sites, is crucial for developing vaccines and therapeutic antibodies, processes that are time-consuming and costly. Accurate prediction of the paratopes binding site can speed up the development by improving our understanding of antibody-antigen interactions. ResultsWe present ParaSurf, a deep learning model that significantly enhances paratope prediction by incorporating both surface geometric and non-geometric factors. Trained and tested on three prominent antibody-antigen benchmarks, ParaSurf achieves state-of-the-art results across nearly all metrics. Unlike models restricted to the variable region, ParaSurf demonstrates the ability to accurately predict binding scores across the entire Fab region of the antibody. Additionally, we conducted an extensive analysis using the largest of the three datasets employed, focusing on three key components: (1) a detailed evaluation of paratope prediction for each Complementarity-Determining Region loop, (2) the performance of models trained exclusively on the heavy chain, and (3) the results of training models solely on the light chain without incorporating data from the heavy chain. Availability and ImplementationSource code for ParaSurf, along with the datasets used, preprocessing pipeline, and trained model weights, are freely available at https://github.com/aggelos-michael-papadopoulos/ParaSurf. Contactangepapa@iti.gr, axenop@iti.gr Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2024

The SARS-CoV-2 envelope PDZ Binding Motif acts as a virulence factor disrupting host's epithelial cell-cell junctions

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for the COVID-19 pandemic, has significantly impacted global health, emphasizing the need to understand its pathogenicity and virulence mechanisms. SARS-CoV-2 disrupts the alveolar epithelial barrier and exacerbates airway inflammation, leading to acute respiratory failure, but the molecular details remain unclear. Additionally, SARS-CoV-2 infection causes neurological symptoms, potentially due to its weakly understood ability to cross the blood-brain barrier. The viral multifunctional Envelope (E) protein is crucial for its virulence, playing a key role in virus assembly, budding, and release. The E protein contains a PDZ-binding motif (PBM) that interacts with host PDZ domain-containing proteins, potentially affecting host signaling pathways and contributing to pathogenicity. This study focuses on the E protein PBM and its role in virulence, disrupting respiratory epithelial barriers and exacerbating airway inflammation. We generated recombinant mutant viruses lacking the PBM and conducted both in vitro and in vivo experiments to elucidate its impact on viral fitness, pathogenicity, and effects on the epithelial integrity. In vitro, the viral mutants showed delayed replication and reduced cytopathic effects. In vivo, experiments with hamsters revealed that PBM-deficient viruses caused less weight loss, lower viral loads, and reduced inflammation, indicating decreased pathogenicity. Histological analyses confirmed less airway damage in these hamsters compared to those infected with the wild-type virus. Additionally, PBM-deficient viruses had impaired interactions with tight junction proteins like ZO-1, a PDZ-containing protein, crucial for maintaining epithelial barrier integrity. Our findings also demonstrate that the PBM does not play a significant role in neuroinvasion during the acute phase of infection, as evidenced by comparable viral RNA loads across brain regions in infected hamsters, regardless of PBM presence. Histopathological and transcriptomic analyses further support this observation, suggesting that the PBM primarily affects specific epithelial barriers. Additionally, RNA-seq analysis on lung and brainstem from infected hamsters reveals that the PBM modulates inflammatory and immune responses, with a stronger impact in lung tissue than in the brainstem. PBM-deficient viruses induce lower levels of inflammation and cytokine expression, suggesting PBMs specific role in enhancing viral pathogenicity through the activation of pathways such as NF-{kappa}B and TNF. Thus, the E protein PBM plays a critical role in SARS-CoV-2s fitness, virulence, and pathogenicity, through the disruption of cell junctions and inflammation, underscoring its potential as a target for therapeutic interventions.

pathology↗

bioRxiv2024

GDNF family receptor alpha-like (GFRAL) expression is restricted to the caudal brainstem

The TGF-{beta} cytokine, growth differentiation factor 15 (GDF15) is a critical mediator of the physiologic response to a range of cellular stresses. While circulating levels of GDF15 are normally very low, these levels increase substantially under a number of acute and chronic pathogenic states including mycotoxin exposure, infection and cancer. GDF15 controls a range of physiologic outputs including reduced appetite, gastric motility, hyperalgesia, emesis, energy expenditure and immune cell function via the GDNF family receptor alpha-like (GFRAL). While the area postrema and nucleus of the solitary tract (AP/NTS) within the caudal brainstem are the only known sites of Gfral-expressing cells, Gfral may also be expressed in other cell types. We therefore utilized single molecule in-situ hybridizations and genetic mouse models to label Gfral-expressing cells from development to adult mouse. With both approaches, we found Gfral-labelled cells in the brainstem and extremely rare Gfral-labelled cells in peripheral tissues in the mouse under normal physiological conditions. Confirming these findings, single nucleus RNA-sequencing of human tissues demonstrated nearly undetectable levels of Gfral mRNA in sites outside the AP/NTS. Our findings confirm AP/NTS neurons are the major site of Gfral expression.

molecular biology↗

bioRxiv2024

Emotional Distractors Capture Attention even at Very Low Contrast Levels: ERP evidence

Emotional visual stimuli, whether appealing or aversive, preferentially capture exogenous attention due to their evolutionary significance. This study assessed whether such capacity persists at low contrast levels, where stimuli are minimally perceived. To this end, we recorded behavioral and electrophysiological (event-related potentials, ERPs) indices of attentional capture from 38 participants who were exposed to negative, neutral, and positive scenes, each presented at four distinct contrast levels. These contrast levels had previously resulted in a correct recognition rate of up to 25%, 50%, 75%, and 100% in a previous sample of 235 participants. Participants were presented with these scenes as distractors while simultaneously performing a perceptual task involving line orientation discrimination. The ERP results confirmed the expected emotional effect on exogenous attention and, critically, unveiled its persistence across all contrast levels. Specifically, occipito-parietal P1 (88-119 ms) was larger for negative than for positive distractors, while in a spreaded N2 component, positive distractors elicited larger amplitudes relative to both negative (213-354 ms) and neutral (213-525 ms) images. These findings reinforce the advantage of emotional distractors in accessing neural processing automatically and highlight the existence of a temporal negativity bias. Importantly, our novel findings emphasize the robustness of this exogenous attention pattern, present even under limited perceptual conditions.

neuroscience↗

bioRxiv2024

An extremely fast neural mechanism to detect emotional visual stimuli: A two-experiment study

Defining the brain mechanisms underlying initial emotional evaluation is a key but unexplored clue to understand affective processing. Event-related potentials (ERPs), especially suited for investigating this issue, were recorded in two experiments (n=36 and n=35). We presented emotionally negative (spiders) and neutral (wheels) silhouettes homogenized regarding their visual parameters. In Experiment 1, stimuli appeared at fixation or in the periphery (200 trials per condition and location), the former eliciting a N40 (39 milliseconds) and a P80 (or C1: 80 milliseconds) component, and the latter only a P80. In Experiment 2, stimuli were presented only at fixation (500 trials per condition). Again, a N40 (45 milliseconds) was observed, followed by a P100 (or P1: 105 milliseconds). Analyses revealed significantly greater N40-C1P1 peak-to-peak amplitudes for spiders in both experiments, and ANCOVAs showed that these effects were not explained by C1P1 alone, but that processes underlying N40 significantly contributed. Source analyses pointed to V1 as a N40 focus (more clearly in Experiment 2). Sources for C1P1 included V1 (P80) and V2/LOC (P80 and P100). These results and their timing point to low-order structures (such as visual thalamic nuclei or superior colliculi) or the visual cortex itself, as candidates for initial evaluation structures.

neuroscience↗

bioRxiv2023

A short sequence in the tail of SARS-CoV-2 envelope protein controls accessibility of its PDZ Binding Motif to the cytoplasm.

The carboxy terminal tail of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) envelope protein (E) contains a PDZ-binding motif (PBM) which is crucial for coronavirus pathogenicity. During SARS-CoV-2 infection, the viral E protein is expressed within the Golgi apparatus membrane of host cells with its PBM facing the cytoplasm. In this work we study the molecular mechanisms controlling the presentation of the PBM to host PDZ (PSD-95/Dlg/ZO-1) domain-containing proteins. We show that at the level of the Golgi apparatus, the PDZ-binding motif of the E protein is not detected by E C-terminal specific antibodies neither by PDZ domain-containing protein binding partner. Four alanine substitutions upstream of the PBM in the central region of the E protein tail is sufficient to generate immunodetection by anti-E antibodies and trigger robust recruitment of the PDZ domain-containing protein into the Golgi organelle. Overall, this work suggests that the presentation of the PBM to the cytoplasm is under conformational regulation mediated by the central region of the E protein tail and that PBM presentation probably does not occur at the surface of Golgi cisternae but likely at post-Golgi stages of the viral cycle.

cell biology↗

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↗

bioRxiv2022

Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants

SUMMARYAnosmia was identified as a hallmark of COVID-19 early in the pandemic, however, with the emergence of variants of concern, the clinical profile induced by SARS-CoV-2 infection has changed, with anosmia being less frequent. Here, we assessed the clinical, olfactory and neuroinflammatory conditions of golden hamsters infected with the original Wuhan SARS-CoV-2 strain, its isogenic ORF7-deletion mutant and three variants: Gamma, Delta, and Omicron/BA.1. We show that infected animals developed a variant-dependent clinical disease including anosmia, and that the ORF7 of SARS-CoV-2 contributes to the induction of olfactory dysfunction. Conversely, all SARS- CoV-2 variants were found to be neuroinvasive, regardless of the clinical presentation they induce. Taken together, this confirms that neuroinvasion and anosmia are independent phenomena upon SARS-CoV-2 infection. Using newly generated nanoluciferase-expressing SARS-CoV-2, we validated the olfactory pathway as a major entry point into the brain in vivo and demonstrated in vitro that SARS-CoV-2 travels retrogradely and anterogradely along axons in microfluidic neuron-epithelial networks. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=151 HEIGHT=200 SRC="FIGDIR/small/505985v2_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@8225ceorg.highwire.dtl.DTLVardef@80342aorg.highwire.dtl.DTLVardef@e0dfd1org.highwire.dtl.DTLVardef@1861e13_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Menstrual cycle and exogenous attention toward emotional expressions

Several studies suggest that the menstrual cycle affects emotional processing. However, these results may be biased by including women with premenstrual syndrome (PMS) in the samples. PMS is characterized by negative emotional symptomatology, such as depression and/or anxiety, during the luteal phase. This study aimed to explore the modulation of exogenous attention to emotional facial expressions as a function of the menstrual cycle in women without PMS. For this purpose, 55 women were selected (from an original volunteer sample of 790) according to rigorous exclusion criteria. Happy, angry, and neutral faces were presented as distractors, while both behavioral performance in a perceptual task and event-related potentials (ERPs) were recorded. This task was applied during both phases of the menstrual cycle (luteal and follicular, counterbalanced), and premenstrual symptomatology was monitored daily. Traditional and Bayesian ANOVAs on behavioral data (reaction times and errors in the task) and ERP indices (P1, N170, N2, and LPP amplitudes) confirmed the expected lack of an interaction of phase and emotion. Taken together, these results indicate that women free of PMS present steady exogenous attention levels to emotionally positive and negative stimuli regardless of the menstrual phase.

neuroscience↗

bioRxiv2021

Interactions of SARS-CoV-2 protein E with cell junctions and polarity PDZ-containing proteins

The C-terminus of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein E contains a PBM (PDZ binding motif) targeting PDZ (PSD-95/Dlg/ZO-1) domains identical to the PBM of SARS-CoV. The latter is involved in the pathogenicity of the virus. Recently, we identified ten human PDZ-containing proteins showing significant interactions with SARS-CoV-2 protein E PBM. We selected several of them involved in cellular junctions and cell polarity (TJP1, PARD3, MLLT4, LNX2) and MPP5/Pals1 previously shown to interact with SARS-CoV E PBM. Targeting cellular junctions and polarity components is a common strategy by viruses to hijack cell machinery to their advantage. In this study, we showed that these host PDZ domains TJP1, PARD3, MLLT4, LNX2 and MPP5/PALS1 interact in a PBM-dependent manner in vitro and colocalize with the full-length E protein in cellulo, sequestrating the PDZ domains to the Golgi compartment. We solved three crystal structures of complexes between human LNX2, MLLT4 and MPP5 PDZs and SARS-CoV-2 E PBM highlighting its binding preferences for several cellular targets. Finally, we showed different affinities for the PDZ domains with the original SARS-CoV-2 C-terminal sequence containing the PBM and the one of the beta variant that contains a mutation close to the PBM. The acquired mutations in E protein localized near the PBM might have important effects both on the structure and the ion-channel activity of the E protein and on the host machinery targeted by the variants during the infection.

biochemistry↗

bioRxiv2021

Fast unconscious processing of emotional stimuli in early stages of the visual cortex

Several cortical and subcortical brain areas have been reported to be sensitive to the emotional content of subliminal stimuli. However, the timing of these activations remains unclear. Our scope was to detect the earliest cortical traces of visual unconscious processing by recording event-related potentials (ERPs) from 43 participants. Subliminal spiders (emotional) and wheels (neutral), sharing similar low-level visual parameters, were presented at two different locations (fixation and periphery). The differential (peak to peak) amplitude from CP1 (77 milliseconds from stimulus onset) to C2 (100 milliseconds), two early visual ERP components originated in V1/V2 according to source localization analyses, was analyzed via Bayesian and traditional analyses. Spiders elicited greater CP1-C2 amplitudes than wheels when presented at fixation. This fast effect of subliminal stimulation -not reported previously to the best of our knowledge-has implications in several debates: i) the amygdala cannot be mediating these effects, ii) latency of other evaluative structures recently proposed, such as the visual thalamus, is compatible with these results, iii) the absence of peripheral stimuli effects points to a relevant role of the parvocellular visual system in unconscious processing.

neuroscience↗