Biology subjects

Conesa, D.

Publications and source records attributed to Conesa, D..

7 recordsLinked to original sources

bioRxiv2026

Calsequestrin localization at RyR2 clusters enables calcium wave propagation in ventricular myocytes

Intracellular calcium waves in cardiac myocytes propagate through a fire-diffuse-fire mechanism in which calcium released from one RyR2 cluster diffuses to neighboring clusters and triggers their activation. Yet propagation faces a fundamental physical difficulty: the calcium signal must cross distances of 1-2 {micro}m between Z-planes while being attenuated by cytosolic buffering and diffusion, and at the same time the release site depletes its local sarcoplasmic reticulum calcium store. How waves propagate efficiently despite these constraints has remained unclear. We developed a three-dimensional computational model of mouse ventricular myocytes at 100 nm resolution to address this question. Our central finding is that co-localization of calsequestrin2 (CASQ2) with RyR2 clusters is required for robust wave propagation. In a physiological model, where CASQ2 is concentrated at release sites as observed experimentally, calcium waves propagate reliably across the cell with velocities that match the experimental range. In contrast, when CASQ2 is distributed uniformly throughout the sarcoplasmic reticulum, keeping total CASQ2 unchanged, the wavefront stalls. These results identify CASQ2-RyR2 co-localization as a key structural requirement for effective calcium wave propagation in ventricular myocytes. Author summaryCalcium waves in cardiomyocytes are thought to underlie the onset of malignant cardiac arrhythmias, such as ventricular tachycardia and fibrillation. Yet, the specific conditions that regulate the transition from local calcium sparks to sustained waves remain poorly understood. Using a newly developed computational model of calcium handling, we demonstrate that the spatial distribution of key regulatory proteins is a critical determinant of arrhythmogenicity. Specifically, we found that calsequestrin2, which buffers Ca2+ within the sarcoplasmic reticulum, must be strictly colocalized with Ca2+ release proteins to facilitate sustained wave propagation. This discovery suggests that cardiac stability depends less on the total quantity of protein and more on its precise architectural organization. The consequences of this finding are significant: it implies that "spatial dysregulation"--where proteins are present but mislocalized--may be a hidden driver of arrhythmias even when protein levels appear normal. This shifts the therapeutic focus from simply altering ion channel conductance to preserving or restoring the structural tethering of the junctional SR. By focusing on the nanodomain architecture, we can better understand how cellular remodeling leads to life-threatening electrical instability.

Cell Biology↗

bioRxiv2026

Resident cardiac macrophages are not required for normal atrioventricular node conduction

Resident cardiac macrophages are understood to facilitate atrioventricular (AV) node conduction because they purportedly couple to AV node myocytes via connexin43 (Cx43) containing gap junctions. We tested this mechanism using biophysical modelling, high-resolution imaging of mouse and human AV conduction tissue, and pharmacological macrophage depletion. In silico, coupling macrophage membrane phenotypes to HCN4+ AV node myocytes imposed an electrotonic load that suppressed pacemaking and promoted conduction slowing, including stable 2:1 block in strand simulations. Anatomically, HCN4-defined components of the mouse AV conduction axis were essentially devoid of Cx43 and overlap of CD68+ macrophages and Cx43 was negligible in both mouse AV node and human penetrating bundle. Finally, near-complete macrophage depletion with CSF1R inhibition (PLX5622) did not alter AV electrical activity in vivo or ex vivo. Together, these data argue against a physiologically relevant role for Cx43-mediated macrophage-myocyte electrical coupling in normal AV node function. HIGHLIGHTSO_LIModelling predicts that AV node automaticity and conduction would be suppressed if macrophages coupled to AV node myocytes C_LIO_LIThe mouse AV conduction axis is essentially devoid of Cx43, currently considered responsible for macrophage-AV node myocyte coupling C_LIO_LIOverlap of macrophages and Cx43 expression is not discernible in the Cx43-expressing human distal AV node C_LIO_LIMacrophage depletion by CSF1R inhibition does not impact AV electrical activity in vivo or ex vivo C_LI

physiology↗

bioRxiv2021

Barrier effects on the spatial distribution of Xylella fastidiosa in Alicante, Spain

Spatial models often assume isotropy and stationarity, implying that spatial dependence is direction invariant and uniform throughout the study area. However, these assumptions are violated when dispersal barriers are present in the form of geographical features or disease control interventions. Despite this, the issue of non-stationarity has been little explored in the context of plant health. The objective of this study was to evaluate the influence of different barriers in the distribution of the quarantine plant pathogenic bacterium Xylella fastidiosa in the demarcated area in Alicante, Spain. Occurrence data from the official surveys in 2018 were analyzed with four spatial Bayesian hierarchical models: i) a stationary model representing a scenario without any control interventions or geographical features; ii) a model with mountains as physical barriers; iii) a model with a continuous or iv) discontinuous perimeter barrier as control interventions surrounding the infested area. Barriers were assumed to be totally impermeable, so they should be interpreted as areas without host plants and in which it is not possible for infected vectors or propagating plant material to pass through. Inference and prediction were performed through the integrated nested Laplace approximation methodology and the stochastic partial differential equation approach. In the stationary model the posterior mean of the spatial range was 4,030.17 m 95% CI (2,907.41, 5,563.88), meaning that host plants that are closer to an infected plant than this distance would be at risk for X. fastidiosa. This distance can be used to define the buffer zone around the infested area in Alicante. In the non-stationary models, the posterior mean of the spatial range varied from 3,860.88 m 95% CI (2,918.61, 5,212.18) in the mountain barrier model to 6,141.08 m 95% CI (4,296.32, 9,042.99) in the continuous barrier model. Compared with the stationary model, the perimeter barrier models decreased the probability of X. fastidiosa presence in the area outside the barrier. Differences between the discontinuous and continuous barrier models showed that breaks in areas with low sampling intensity resulted in a higher probability of X. fastidiosa presence. These results may help authorities prioritize the areas for surveillance and implementation of control measures.

pathology↗

bioRxiv2021

Designing fisheries restricted areas using standard fishery survey data: a novel multilevel spatio-temporal approach

Marine Protected Areas (MPAs) are a promising management tool for the conservation and recovery of marine ecosystems, as well as fisheries management. MPAs are generally established as permanent closures but marine systems are dynamic, which has generated debate in favour of more dynamic designs. As a consequence, the identification of priority areas should assess their persistence in space and time. Here, we develop a step-by-step approach to assess the spatiotemporal dynamics of fisheries management priority areas using standard fishery-independent survey data. To do so, we fit Bayesian hierarchical spatiotemporal SDM models to different commercially important demersal species and use the resulting maps to fit different spatial prioritisation configurations. We use these results to assess the spatiotemporal dynamics of fisheries priority areas. The proposed method is illustrated through a western Mediterranean case study using fishery-independent trawl survey data on six commercially important species collected over 17 years. We identified two fisheries priority area patterns in the study area, each predominant during a different time-period of the study, asserting the importance of regularly re-assessing MPA designs.

ecology↗

bioRxiv2020

Tracking the outbreak. An optimized delimiting survey strategy for Xylella fastidiosa.

O_LICurrent legislation enforces the implementation of intensive surveillance programs for quarantine plant pathogens. After an outbreak, surveys are implemented to delimit the geographic extent of the pathogen and execute disease control. The feasibility of control programs is highly dependent on budget availability, thus it is necessary to target and optimize surveillance strategies. C_LIO_LIA sequential adaptive delimiting survey involving a three-phase and a two-phase design with increasing spatial resolution was developed and implemented for the Xylella fastidiosa outbreak in Alicante, Spain. Inspection and sampling intensities were optimized using simulation-based methods and results were validated using Bayesian spatial models. C_LIO_LIThis strategy made it possible to sequence inspection and sampling considering different spatial resolutions, and to adapt the inspection and sampling intensity according to the information obtained in the previous, coarser, spatial resolution. C_LIO_LIThe proposed strategy was able to delimit efficiently the extent of Xf improving efficiency of the current in terms of survey efforts. From a methodological perspective, our approach provides new insights of alternative delimiting designs and new reference sampling intensity values. C_LI

pathology↗

bioRxiv2019

Two-variable nullcline analysis of ionic general equilibrium predicts calcium homeostasis in ventricular myocytes

AbstractVentricular contraction is roughly proportional to the amount of calcium released from the Sarcoplasmic Reticulum (SR) during systole. While it is rather straightforward to measure calcium levels and contractibility under different physiological condition, the complexity of calcium handling during systole and diastole has made the prediction of its release at steady state impossible. Here we approach the problem analyzing the evolution of intracellular and extracellular calcium fluxes during a single beat which is away from homeostatic balance. Using an in-silico subcellular model of rabbit ventricular myocyte, we show that the high dimensional nonlinear problem of finding the steady state can be reduced to a two-variable general equilibrium condition where pre-systolic calcium level in the cytosol and in the SR must fulfill simultaneously two different equalities. This renders calcium homeostasis as a problem that can be studied in terms of its equilibrium structure, leading to precise predictions of steady state from single-beat measurements. We show how changes in ionic channels modify the general equilibrium as shocks would do in general equilibrium macroeconomic models. This allows us to predict when an enhanced entrance of calcium in the cell reduces its contractibility and explain why SERCA gene therapy, a change in calcium handling to treat heart failure, might fail to improve contraction even when it successfully increases SERCA expression. Author summaryCardiomyocytes, upon voltage excitation, release calcium, which leads to cell contraction. However, under some pathological conditions, calcium handling is impaired. Recently, SERCA gene therapy, whose aim is to improve Ca2+ sequestration by the Sarcoplasmic Reticulum (SR), has failed to improve the prognosis of patients with Heart Failure. This, together with recent counterintuitive results in calcium handling, has highlighted the need for a framework to understand calcium homeostasis across species and pathologies. We show here that the proper framework is a general equilibrium approach of two independent variables. The development of this framework allows us to find a possible mechanism for the failure of SERCA gene therapy even when it manages to increase Ca SERCA expression.

systems biology↗

bioRxiv2019

Modelling Inoculum Availability of Plurivorosphaerella nawae in Persimmon Leaf Litter with Bayesian Beta Regression

Circular leaf spot (CLS), caused by Plurivorosphaerella nawae, is a serious disease of persimmon (Diospyros kaki) inducing necrotic lesions on leaves, defoliation and fruit drop. Under Mediter-ranean conditions, P. nawae forms pseudothecia in the leaf litter during winter and ascospores are released in spring infecting susceptible leaves. Persimmon growers are advised to apply fungicides for CLS control during the period of inoculum availability, which was defined based on ascospore counts under the microscope. A model of inoculum availability of P. nawae was developed and evaluated as an alternative to ascospore counts. Leaf litter samples were collected weekly in LAlcudia from 2010 to 2015. Leaves were soaked, placed in a wind tunnel, and released ascospores of P. nawae were counted. Hierarchical Bayesian beta regression methods were used to fit the dynamics of ascospore production in the leaf litter. The selected model, having the lowest values of DIC, WAIC and LCPO, included accumulated degree days (ADD) and ADD taking into account the vapor pressure deficit (ADDvpd) as fixed effects, and year as a random effect. This model had a MAE of 0.042 and RMSE of 0.062. The beta regression model was evaluated in four orchards for different years from 2010 to 2015. Higher accuracy was obtained at the beginning and the end of the ascospore production period, which are the events of interest to schedule fungicide sprays for CLS control in Spain. This same modelling framework can be extended to other fungal plant pathogens whose inoculum dynamics are expressed as proportion data.

pathology↗