Biology subjects

Santamaria, A.

Publications and source records attributed to Santamaria, A..

9 recordsLinked to original sources

bioRxiv2026

Curating MitoCore: A Standardized Small-Scale Human Metabolic Model as Platform for Proteomics Integration and Disease Modeling

MotivationCentral human metabolism powers cellular processes, yet its dysregulation in disease remains poorly understood. While comprehensive genome-scale metabolic models like Human-GEM are available, their size limits interpretability and computational efficiency. Conversely, the smaller MitoCore model is more manageable but lacks the standardized annotations and curated gene-protein-reaction (GPR) associations necessary for omics integration like protein-constrained modeling. Improving MitoCores annotation quality is therefore essential for its use in integrative workflows. ResultsWe systematically updated MitoCore to enhance compatibility with the protein-constrained modeling framework sMO-MENT. By restructuring legacy annotations and integrating data from Human-GEM and MitoMammal, we increased EC-codes from 354 to 593 and UniProt-annotated genes from 0 to 592. MitoCore captures central metabolic processes, confirmed by mapping its reactions to 51 of 106 metabolic KEGG modules. Integration of thrombocyte proteomics and experimental ATP data for original and curated models showed an increase in mapped proteins (228 to 294) and reactions with kcat values (295 to 310), adding 33 protein-constrained reactions. Consequently, prediction errors for exchange fluxes and ATP production decreased by 19% and 89%, respectively, with 100% of ATP predictions falling within the 95% confidence interval (compared to 16% for the original model). Finally, we implemented a continuous integration/continuous deployment pipeline for automated updates from future Human-GEM releases. These improvements provide a computationally efficient, well-annotated model for studying central metabolism across human cell types. Availability and ImplementationAll source code for reproducing results from this paper is available at https://doi.org/10.5281/zenodo.20813825.

Systems Biology↗

bioRxiv2025

Effects of aperiodic neural activity on sleep-based emotional memory consolidation across the lifespan

Sleep neurophysiology undergoes significant changes across the lifespan, which coincide with age-related differences in memory, particularly for emotional information. However, the mechanisms that underlie these effects remain poorly understood. One potential mechanism is the aperiodic component, which reflects "neural noise", differs across age, and is predictive of perceptual and cognitive processes. In this study, we investigated how intrinsic (i.e., resting-state) aperiodic neural activity modulates sleep-based emotional memory consolidation across the human lifespan. In a within-subjects, repeated measures design, forty-two participants aged 7 - 72 years (M = 26.60, SD = 17.45; 26 female) completed a learning and baseline recognition emotional memory task before a 2hr afternoon sleep opportunity and an equivalent period of wake. Recognition accuracy was also assessed post-delay. We found that aperiodic slopes follow a u-shaped trajectory across the lifespan: slopes flatten from childhood to young adulthood, before steepening thereafter, with this effect most prominent in frontal regions. Age-related differences in aperiodic slopes also explained interindividual differences in emotional memory consolidation, with less age-related flattening of slopes associated with stronger consolidation of negative stimuli post-sleep but not post-wake. Lastly, independent of aperiodic activity, age-related differences in NREM oscillatory activity predicted emotional memory consolidation. These findings suggest that the efficiency of sleep-based emotional memory consolidation is modulated by age-related differences in aperiodic neural and NREM oscillatory activities, providing novel insights into the neurophysiological mechanisms underpinning emotional memory across the lifespan.

neuroscience↗

bioRxiv2024

Untangling structural molecular details of the endocytic adaptor protein CALM upon binding with phosphatidylinositol 4,5-bisphosphate-containing model membranes

Clathrin assembly lymphoid myeloid leukemia protein (CALM) is involved in the formation of clathrin-mediated endocytic coats by virtue of binding many proteins involved in the process, including clathrin itself and AP2 cargo adaptor complex. CALM is able to specifically recognize the inner leaflet of the plasma membrane by binding the membranes phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). Here, a biophysical approach, primarily using neutron and X-ray scattering and solid-state NMR experiments, was exploited to investigate CALM interaction with PtdIns(4,5)P2-presenting model membranes. The presented experimental data reveal how the CALM folded domain is partly accommodated within the lipid membrane, directly interacting with PtdIns(4,5)P2 phosphates. Moreover, these data suggest that CALMs amphiphilic N-terminal helix buries into the membrane, not only stabilising the protein docking to the membrane but also providing a mechanism to induce membrane curvature.

biophysics↗

bioRxiv2024

Combined thermodynamic and time-resolved structural analysis of interactions between AP2 and biomimetic plasma membranes provides insights into clathrin-mediated endocytosis

Clathrin mediated endocytosis (CME) is the main mechanism for swift and selective uptake of proteins into eukaryotic cells. CME is initiated by recruitment to the plasma membrane (PM) of the adaptor protein AP2, which recognizes the PM-associated lipid PtdIns(4,5)P2, as well as the protein cargo to be internalized. Nonetheless, many aspects of this process remain unclear due to their in vivo complexity. Here, a thermodynamic and time-resolved structural analysis of AP2 binding to different biomimetic PM was undertaken under physiological conditions using a combination of neutron reflectometry, interfacial tensiometry and rheology, and atomic force microscopy. The resultant in vitro data replicated previous in vivo observations, as well as yielded biophysical insights into normal and aborted CME. The presence of cargo may not be pivotal for the "activating" conformational change of AP2. However, the presence of cargo extends AP2s residence time on the membrane surface, due to slower on- and off-rates, thereby tentatively giving sufficient time for CME to proceed fully. Moreover, upon interaction with AP2, phospholipid lateral diffusion decreases markedly, inducing a gel phase attributed to creating a percolated network involving AP2 on the membrane, which could potentially serve as a mechanism for modulating subsequent clathrin binding.

biophysics↗

bioRxiv2023

Circulating tumor extracellular vesicles to monitor metastatic prostate cancer genomics and transcriptomic evolution

Extracellular vesicles (EVs) secreted by tumors are abundant in plasma, but their potential for interrogating the molecular features of tumors through multi-omic profiling remains widely unexplored. Genomic and transcriptomic profiling of circulating EV-DNA and EV-RNA isolated from a range of in-vitro and in-vivo models of metastatic prostate cancer (mPC) revealed a high contribution of tumor material to EV-loaded DNA/RNA. Findings were validated in a cohort of longitudinal plasma samples collected from mPC patients during androgen receptor signaling inhibitor (ARSI) therapy. EV-DNA genomic features recapitulated matched-patient biopsies and associated with clinical progression. We developed a novel approach to enable the transcriptomic profiling of EV-RNA (RExCuE). We report how the transcriptomic profile in mPC EV-RNA is enriched for tumor-associated transcripts when compared to same patient blood RNA and healthy individuals EV-RNA, and reflect early on-therapy tumor adaptation changes. Altogether, we show that EV profiling enables longitudinal transcriptomic and genomic profiling of mPC in liquid biopsy.

cancer biology↗

bioRxiv2021

Reconfigurations in brain networks upon awakening from slow wave sleep: Interventions and implications in neural communication

Sleep inertia is the brief period of impaired alertness and performance experienced immediately after waking. While the neurobehavioral symptoms of sleep inertia are well-described, less is known about the neural mechanisms underlying this phenomenon. A better understanding of the neural processes during sleep inertia may offer insight into the cognitive impairments observed and the awakening process generally. We observed brain activity following abrupt awakening from slow wave sleep during the biological night. Using electroencephalography (EEG) and a network science approach, we evaluated power, clustering coefficient, and path length across frequency bands under both a control condition and a blue-enriched light intervention condition in a within-subject design. We found that under control conditions, the awakening brain is typified by an immediate reduction in global theta, alpha, and beta power. Simultaneously, we observed a decrease in the clustering coefficient and an increase in path length within the delta band. Exposure to blue-enriched light immediately after awakening ameliorated these changes, but only for clustering. Our results suggest that long-range network communication within the brain is crucial to the waking process and that the brain may prioritize these long-range connections during this transitional state. Our study highlights a novel neurophysiological signature of the awakening brain and provides a potential mechanistic explanation for the effect of light in improving performance after waking. One sentence summaryBlue-enriched light partially accelerates the rapid prioritization of long-range communication within the human brain that characterizes sleep inertia

neuroscience↗

bioRxiv2021

Strikingly different roles of SARS-CoV-2 fusion peptides uncovered by neutron scattering

Coronavirus disease-2019 (COVID-19), a lethal respiratory illness caused by the coronavirus SARS-CoV-2, emerged in the end of 2019 and has since spread aggressively across the globe. A thorough understanding of the molecular mechanisms of cellular infection by coronaviruses is therefore of utmost importance. A critical stage in infection is the fusion between viral and host membranes. Here, we present a detailed investigation of the role of the SARS-CoV-2 Spike protein, and the influence of calcium and cholesterol, in this fusion process. Structural information from specular neutron reflectometry and small angle neutron scattering, complemented by dynamics information from quasi-elastic and spin-echo neutron spectroscopy, revealed strikingly different functions encoded in the Spike fusion domain. Calcium drives the N-terminal of the Spike fusion domain to fully cross the host plasma membrane. Removing calcium however re-orients the protein to the lipid leaflet in contact with the virus, leading to significant changes in lipid fluidity and rigidity. In conjunction with other regions of the fusion domain which are also positioned to bridge and dehydrate viral and host membranes, the molecular events leading to cell entry by SARS-CoV-2 are proposed. SIGNIFICANCEWe have recreated here important elements of the critical membrane fusion mechanism of the SARS-CoV-2 coronavirus by simplifying the system down to its core elements, amenable to experimental analysis by neutron scattering. Neutrons are well suited for the study of protein - membrane interactions under physiological conditions, since they allow structural and dynamics characterization at room temperature. Our results revealed strikingly different functions encoded in the viral Spike fusion domain and thereby provide a potential calcium-dependent cell entry mechanism for SARS-CoV-2. In particular, calcium drives the proteins N-terminal to harpoon through the host membrane, while removing calcium re-orients the protein so that it is able to bridge and dehydrate lipid membranes, facilitating their fusion.

biophysics↗

bioRxiv2018

Attention and Emotion-Enhanced Memory: A Systematic Review and Meta-Analysis of Behavioural and Neuroimaging Evidence

The interaction between attention and emotion is posited to influence long-term memory consolidation. We systematically reviewed experiments investigating the influence of attention on emotional memory to determine: (i) the reported effect of attention on memory for emotional stimuli, and (ii) whether there is homogeneity between behavioural and neuroimaging based effects. Over half of the 47 included experiments found a moderate-to-large effect of attention on emotional memory as measured behaviourally. However, eye-tracking research provide mixed support for the role of attention-related processes in facilitating emotional information into long-term memory. Similarly, modulations in sensory-related components at encoding were not predictive of long-term memory formation, whereas later components appear to differentially reflect the allocation of attention to heterogeneous emotional stimuli. This dissociation in neurophysiology is paralleled by the activation of distinct neural networks under full- and divided-attention conditions. We quantified the effects of the behavioural, eye-tracking and neuroimaging findings via meta-analysis to show that the neural substrates of attention-related emotional memory enhancement may be sensitive to specific methodological parameters.

neuroscience↗

bioRxiv2017

Alpha Oscillatory Activity Prior to Encoding Modulates Memory Consolidation during Wake but not Sleep

Sleep promotes memory consolidation through unique neuromodulatory activity. However, little is known about the impact of attention during pre-sleep memory encoding on later memory performance. The current study aimed to address the question of whether attentional state prior to encoding, as indexed by alpha oscillatory activity, modulates the consolidation of images across periods of sleep and wake. 22 participants aged 18 - 41 years (mean age = 27.3) viewed 120 emotionally valenced images (positive, negative, neutral) before a 2hr afternoon sleep opportunity and an equivalent period of wake. Following the sleep and wake conditions, participants were required to distinguish between 120 previously seen (target) images and 120 new (distractor) images. Relative alpha power - adjusted according to participants individual alpha frequency - was computed to index attentional state prior to the learning phase. Generalised linear mixed-effects modelling revealed memory performance was modulated by attention, such that greater pre-encoding alpha power preferentially promoted memory consolidation during wake compared to sleep. There was no difference in memory performance between positive, negative and neutral stimuli. Modulations in alpha oscillatory activity may help to coordinate the flow of information between task-relevant cortical regions and a thalamo-cortical loop that preferentially subserves the formation of memory during times of wake relative to sleep.

neuroscience↗