Biology subjects

Cerda, M.

Publications and source records attributed to Cerda, M..

6 recordsLinked to original sources

bioRxiv2025

Persistent Immune Dysregulation during Post-Acute Sequelae of COVID-19 is Manifested in Antibodies Targeting Envelope and Nucleocapsid Proteins

Post-Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome or "Long COVID" represents a widespread health challenge that necessitates the development of novel diagnostic approaches and targeted therapies that can be readily deployed. Immune dysregulation has been reported as one of the hallmarks of PASC, but the extent of PASC immune dysregulation in patients over time remains unclear. We therefore assessed SARS-CoV-2-specific antibody responses, peripheral immune cell profiles, autoantibody profiles and circulating cytokines for up to 6 months in participants with a SARS-CoV-2 infection who either convalesced or developed PASC. Compared to convalescent, PASC participants with a broad range of PASC phenotypes exhibited persistently elevated IgG titers for SARS-CoV-2 Envelope and Nucleocapsid proteins over the 6 months of study duration. In contrast, the IgG responses to Spike protein were significantly lower in the PASC cohort with predominantly IgG1 and IgG3 class-switched bias. Using CyTOF analysis, we show elevated numbers of circulating T follicular helper cells (cTFH) and mucosa-associated invariant T cells (MAIT), which also correlated with high anti-Envelope IgG titers. Persistent immune activation was accompanied by augmented serum cytokine profiles with LIF, IL-11, Eotaxin-3, and HMGB-1 in PASC participants, who also demonstrated significantly higher rates of autoantibodies. These findings highlight the persistence of immune dysregulation in PASC, underscoring the need to explore targeted therapies addressing viral persistence, dysregulated antibody production, and autoimmunity.

immunology↗

bioRxiv2024

AI-assisted imaging screening reveals mechano-molecular tissue organizers and network of signaling hubs.

Cadherin-mediated adhesions are crucial mechanical and signaling hubs that connect cells within a tissue and probe the mechanics of the surrounding environment. They constitute a physical link between the actin cytoskeleton of neighboring cells, providing the mechanical coordination needed for morphogenetic processes, tissue homeostasis, collective migration, and regeneration. Disruptions in adhesion mechanisms are closely linked to the breakdown of epithelial structure and the emergence of disease-related traits characteristic of cancer progression. The cadhesome network comprises over 170 structural and regulatory proteins involved in cadherin-mediated adhesion. While this network is essential for coordinating tissue responses to mechanical stress, its complexity has historically limited our understanding of how individual components contribute to force transmission and tissue homeostasis. Recent technological advances offer tools to investigate large molecular networks in cellular function and pathology (functional omics). Leveraging these advances, we developed an experimental and analytical platform combining high-throughput gene silencing, imaging, and artificial intelligence (AI) to systematically profile each role of each protein in tissue formation, mechanical stability, and response to induced tension. Using EpH4 cells as an epithelial tissue model, we performed systematic silencing in triplicate, capturing a range of tissue phenotypes under baseline and tension-inducing conditions. Machine learning methods were used to analyze complex imaging data, quantify tissue ruptures, characterize junctional organization, and measure tension states of the tissue. By incorporating machine learning algorithms, we automated image feature extraction, clustering, and classification, enabling an unprecedented quantitative evaluation of tissue mechanics at scale. Our machine learning models allowed us to identify significant patterns, including protein-specific responses to tension and their roles in tissue-level mechanical integrity. Finally, we constructed a protein interaction network detailing the roles of each protein, their physical interactions, and known links to cancer. The network analysis revealed three prominent mechanotransductive and signaling subnetworks centered around E-cadherin, EGFR, and RAC1. Our study provides a foundational framework for investigating mechanosensing proteins and it offers a scalable blueprint for discovering potential therapeutic targets in diseases like cancer, where tissue mechanics play a crucial role. TeaserAI-aided screening identifies key regulators of epithelial tissue mechanics, uncovering potential therapeutic targets in cancer.

cell biology↗

bioRxiv2024

Impact of cardiometabolic factors and blood beta-amyloid on the volume of white matter hyperintensities in dementia-free subjects with cognitive complaints

IntroductionWhite matter hyperintensities (WMH) in Alzheimers disease (AD) have traditionally been associated with cerebrovascular diseases. Amyloid {beta} (A{beta}) deposition reportedly contributes to WMHs; however, this relationship remains unclear in dementia-free subjects with cognitive complaints (CC). Here, we explored the relationship between WMHs and cardiometabolic and A{beta} blood biomarkers in a community-based cohort of Latin American CC participants. MethodsWe recruited 112 individuals with CC (69 - 92 YO, 90 females) with available plasma A{beta} biomarkers and cardiometabolic markers (systolic - diastolic blood pressure and glycaemia). WMHs were quantified using a lesion segmentation tool based on SPM12 and segmented using the John Hopkins University (JHU) Atlas and ALVIN segmentation for periventricular and subcortical white matter. Linear multiple regression models were fitted to assess total WMH lesions and the segmented tract, using demographics, cardiometabolic, and A{beta} blood biomarker measures as independent variables. ResultsAfter multiple comparison corrections, diastolic blood pressure was associated with WMHs, specifically in the right anterior thalamic radiation, left cingulum, minor forceps, and subcortical ALVIN segmentation. Glycaemia was associated with WMH volume in forceps major, forceps minor, and right fronto-occipital fasciculi. Conversely, A{beta} blood biomarkers and systolic blood pressure showed no association with WMH overall or in specific tracts. ConclusionOur findings suggest that, in dementia-free CC individuals, WMH volume was more related to cardiometabolic factors, whereas A{beta} blood biomarkers might be of less relevance. Dementia prevention strategies in individuals might be a useful focus for managing high peripheral vessel resistance and endothelial damage due to hypertension and hyperglycaemia.

neuroscience↗

bioRxiv2023

Cochlear dysfunction as an early biomarker for cognitive decline in normal hearing and mild hearing loss

Age-related hearing loss (presbycusis) at moderate levels (>40 dB HL) has been recognized as an important risk factor for cognitive decline. However, whether individuals with mild hearing loss (audiogram thresholds between 25 and 40 dB HL) or even those with normal audiograms (<25 dB HL) have a higher risk of dementia, is still debated. Importantly, these early stages of presbycusis are the most common among the elderly, indicating the need to screen and identify individuals with early presbycusis that have an increased risk of cognitive decline. Unfortunately, in this group of patients, audiogram thresholds are not sufficiently sensitive to detect all the hearing impairments that are related to cognitive decline. Consequently, at the individual level, audiogram thresholds are not good estimators of the dementia risk in the group with mild hearing loss or normal hearing thresholds. Here, we propose to use distortion product otoacoustic emissions (DPOAE), as an objective and sensitive tool to estimate the risk of clinically relevant cognitive decline in elders with normal hearing o mild hearing loss. We assessed neuropsychological, brain magnetic resonance imaging, and auditory analyses on 94 subjects aged >64 years old. In addition, cognitive and functional performance was evaluated with the Clinical Dementia Rating Sum of Boxes (CDR SoB), assessed through structured interviews conducted by neurologists, who were blind to the DPOAE results. We found that cochlear dysfunction, measured by DPOAE -and not by conventional audiometry-, was associated with CDR SoB classification and brain atrophy in the group with mild hearing loss (25 to 40 dB), and normal hearing (<25 dB). Our findings suggest that DPOAE may be a non-invasive tool for detecting neurodegeneration and cognitive decline in the elderly, potentially allowing for early intervention.

neuroscience↗

bioRxiv2021

The Dendritic Ergic: Microtubule And Actin Cytoskeletons Mediate Stop-And-Go Movement Of Mobile Carriers Between Stable Structures

The ER-to-Golgi intermediate compartment (ERGIC) is a membranous organelle that mediates protein transport between the endoplasmic reticulum (ER) and Golgi apparatus. In neurons, clusters of these vesiculotubular structures are situated in throughout the cell in proximity to the ER, passing cargo to the cis-Golgi cisternae located mainly in the perinuclear region. Although ERGIC markers have been identified in neurons, the distribution and dynamics of neuronal ERGIC structures have not been characterized. Here, we argue that long-distance ERGIC transport occurs via an intermittent mechanism in neurons, with mobile elements moving between stationary structures. Using immunofluorescence microscopy, we detected discrete, irregular ERGIC structures in neural soma and dendrites. Slow live-cell imaging (2 frames/minute; 15 minutes) indicated that 8% of dendritic ERGIC structures were stable, remaining in place over long periods. On the other hand, fast live-cell imaging (2 frames/second; 180 seconds) captured mobile ERGIC structures advancing very short distances along dendrites. Importantly, these distances were consistent with the lengths between the stationary ERGIC structures. Kymography revealed ERGIC elements that moved intermittently, emerging from and fusing with stationary ERGIC structures. Surprisingly, this movement was apparently dependent not only on the integrity of the microtubule cytoskeleton, as has been previously reported, but on the actin cytoskeleton as well. Our results indicate that the dendritic ERGIC has a dual nature, with both stationary and mobile structures. The neural ERGIC network transports proteins via a stop-and-go movement that is mediated by the microtubule and actin cytoskeletons.

cell biology↗

bioRxiv2018

Cdh2 coordinates Myosin-II dependent internalisation of the zebrafish neural plate

Tissue internalisation is a key morphogenetic mechanism by which embryonic tissues generate complex internal organs and a number of studies of epithelia have outlined a general view of tissue internalisation. Here we have used quantitative live imaging and mutant analysis to determine whether similar mechanisms are responsible for internalisation in a tissue that apparently does not have a typical epithelial organisation - the zebrafish neural plate. We found that although zebrafish embryos begin neurulation without a conventional epithelium, medially located neural plate cells adopt strategies typical of epithelia in order to constrict their dorsal surface membrane during cell internalisation. Furthermore, we show that Myosin-II activity is a significant driver of this transient cell remodeling which also depends on Cdh2 (N-cadherin). Abrogation of Cdh2 results in defective Myosin-II distribution, mislocalised internalisation events and defective neural plate morphogenesis. Our work suggests Cdh2 coordinates Myosin-II dependent internalisation of the zebrafish neural plate.

developmental biology↗