Artículos (Fisiología Médica y Biofísica)

URI permanente para esta colecciónhttps://hdl.handle.net/11441/11035

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Profiling brain morphology for autism spectrum disorder with two cross-culture large-scale consortia
(Nature Publishing Group, 2025-08-05) Fan, Xue-Ru; He, Ye; Wang, Yin-Shan; Li, Lei; China Autism Brain Imaging Consortium (CABIC); Xujun, Duan; Xi-Nian, Zuo; Lifespan Brain Chart Consortium (LBCC); Romero García, Rafael; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
We explore neurodevelopmental heterogeneity in Autism Spectrum Disorder (ASD) through normative modeling of cross-cultural cohorts. By leveraging large-scale datasets from Autism Brain Imaging Data Exchange (ABIDE) and China Autism Brain Imaging Consortium (CABIC), our model identifies two ASD subgroups with distinct brain morphological abnormalities: subgroup “L” is characterized by generally smaller brain region volumes and higher rates of abnormality, while subgroup “H” exhibits larger volumes with less pronounced deviations in specific areas. Key areas, such as the isthmus cingulate and transverse temporal gyrus, were identified as critical for subgroup differentiation and ASD trait correlations. In subgroup H, the regional volume of the isthmus cingulate cortex showed a direct correlation with individuals’ autistic mannerisms, potentially corresponding to its slower post-peak volumetric declines during development. These findings offer insights into the biological mechanisms underlying ASD and support the advancement of subgroup-driven precision clinical practices.
Trasplantes de agregados celulares del cuerpo carotídeo en modelos animales de enfermedad de Parkinson
(Elsevier, 2000) Toledo Aral, Juan José; Méndez-Ferrer, Simón; Pardal Redondo, Ricardo; López Barneo, José; Fisiología Médica y Biofísica; CTS517: Fisiología Molecular; CTS516: Fisiología Celular y Biofísica; CTS007: Fisiopatología de Células Madre Neurales
La enfermedad de Parkinson se produce como resultado de la degeneración progresiva de las neuronas dopaminérgicas de la sustancia negra que inervan el estriado, por lo que una de las aproximaciones terapéuticas a esta enfermedad ha sido el trasplante intraestriatal de células dopaminérgicas. Durante los últimos años hemos investigado si las células glómicas del cuerpo carotídeo podrían servir como fuente de dopamina en modelos de enfermedad de Parkinson en ratas y monos. Hemos usado ratas hechas hemiparkinsonianas por inyección unilateral de hidroxidopamlna en la sustancia negra y monos con parkinsonismo bilateral crónico tratados con MPTP. En ambos casos se hicieron implantes unilaterales en el putamen de agregados celulares de tejido del cuerpo carotídeo. Unas pocas semanas después del trasplante se observó recuperación funcional de los animales que se mantuvo durante varios meses. Aunque el estudio ha sido mucho más detallado en ratas, en los dos modelos animnles de enfermedad de Parkinson la mejoría de los déficit motores se acompaño de una supervivencia de las células glómicas implantadas y de reinervación dopaminérgica del estrido. Nuestra› trabajo actual se centra en la caracterización de los mecanismos moleculares responsables de la supervivencia de lris células glómicas y de sus efectos sobre las neuronas nigroestriatales. Nuestros resultados sugieren que el autotrasplante intraestriatal de tejido del cuerpo carotídeo podría ser una técnica de elección para el tratamiento de algunos casos de enfermedad de Parkinson en el hombre.
NO-immune privilege for hematopoietic stem cells
(Inst biochemistry & Cell biology; Springer nature, 2025-02-28) Chédeville, Agathe L.; Méndez-Ferrer, Simón; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS); Ministerio de Ciencia, Innovación y Universidades (España)
Ins and outs of HSCs and VEGF-induced vascular remodeling: Toward improved HSC mobilization and engraftment
(Cell press; Elsevier BV, 2025-07-08) Caduc, Madeline J.; Méndez-Ferrer, Simón; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS); Servicio Alemán de Intercambio Académico (DAAD); Programa de Becas Mildred Scheel para la Investigación del Cáncer; Plan de Investigación Científica, Técnica y de Innovación, Ministerio de Ciencia, Innovación y Universidades, Gobierno de España
Neuronal lipofuscinosis caused by Kufs disease/CLN4 DNAJC5 mutations but not by a CSPα/DNAJC5 deficiency
(Amer Assoc Advancement Science, 2025-03) López-Begines, Santiago; Borjini, Nozha; Lavado-Roldán, Ángela; Mesa-Cruz, Cristina; Mavillard, Fabiola; Nieto González, José L.; Fernández-Chacón, Rafael; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS); Junta de Andalucía; Junta de Castilla-La Mancha; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agencia Estatal de Investigación. España
Kufs disease/CLN4 is an autosomal dominant neurodegenerative disorder caused by unknown mechanisms through Leu115Arg and Leu116Δ mutations in the DNAJC5 gene that encodes the synaptic vesicle co-chaperone cysteine string protein α (CSPα/DNAJC5). To investigate the disease mechanisms in vivo, we generated three independent mouse lines overexpressing different versions of CSPα/DNAJC5 under the neuron-specific Thy1 promoter: wild-type (WT), Leu115Arg, and Leu116Δ. Mice expressing mutant Leu115Arg CSPα/DNAJC5 are viable but develop motor deficits. As described in patients with Kufs disease, we observed the pathological lipofuscinosis and intracellular structures resembling granular osmiophilic deposits (GRODs) in the mutant but not in the WT transgenic lines. Microglia engulf lipofuscin and lipofuscin-containing neurons. Notably, conventional or conditional knockout mice lacking CSPα/DNAJC5 did not exhibit any signs of increased lipofuscinosis or GRODs. Our novel mouse models provide a valuable tool to investigate the molecular mechanisms underlying Kufs disease/CLN4. DNAJC5 mutations cause neuronal lipofuscinosis through a cell-autonomous gain of a pathological function of CSPα/DNAJC5.
IncRNA ADEPTR loss-of-function elicits sex-specific behavioral and spine déficits
(Cell Press, 2025-08-15) Chanda, Kaushik; Carter, Jackson P.; Nishizono, Hirofumi; Raveendra, Bindu L.; Brantley, Alicia; Grinman, Eddie; Espadas, Isabel; Puthanveettil, Sathyanarayanan V; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
Activity-dependent neuronal changes are critical for learning and memory, but the role of long noncoding RNAs (lncRNAs) in these processes is under active investigation. In this study we investigated ADEPTR, a dendritically localized, cAMP-modulated lncRNA essential for synapse morphology. Using two mouse models—one with ADEPTR deletion (L-ADEPTR) and another lacking its protein interaction domain (S-ADEPTR)—we examined sex-specific effects on behavior and neuronal architecture. Behavioral tests showed reduced anxiety in S-ADEPTR adult male mice, with no learning or memory deficits in either model. Neuronal cultures and brain samples from various developmental stages revealed morphological impairments in both sexes. Notably, L-ADEPTR female mice had fewer thin spines in the hippocampal CA1 region at postnatal day 42. Despite these structural deficits, increased expression of plasticity-related genes BDNF and cFOS in the cortex and hippocampus suggests compensatory mechanisms
Innate immune mechanisms hijacked by leukemia-initiating stem cells for selective advantage and immune evasion in Ptpn11-associated JMML
(Cell Press, 2025-08-26) Zheng, Hongrong; Zhao, Peng; Tan, Zhenya; Yu, Wen-Mei; Werner, Juwita; Stieglitz, Elliot; Méndez-Ferrer, Simón; Qu, Cheng-Kui; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
Juvenile myelomonocytic leukemia (JMML) originates from mutated hematopoietic stem cells. The mechanism by which mutant stem cells are sustained, leading to leukemia development, remains elusive. By comprehensively examining transcriptomic profiles, cell compositions, developmental trajectories, and cell-cell interactions across various stages of tumor cell development in a mouse model of Ptpn11 mutation-associated JMML, we find that Ptpn11E76K/+ mutant stem cells exhibit de novo activation of the myeloid transcriptional program and markedly increased expression of innate immunity-associated antimicrobial peptides and pro-inflammatory proteins, particularly S100a9 and S100a8. Biological experiments confirm that S100a9/S100a8 confer a selective advantage to mutant stem cells through autocrine effects and facilitate immune evasion by recruiting and promoting immune-suppressive myeloid-derived suppressor cells in the microenvironment. Importantly, pharmacological inhibition of S100a9/S100a8 signaling effectively impede leukemia development from Ptpn11E76K/+ mutant stem cells. These findings collectively suggest that JMML-initiating cells exploit innate immune and inflammatory mechanisms to establish clonal dominance.
Genetic map of the carotid body stem cell niche with focus on the O2-sensing chemoreceptor cell lineage
(Nature Publishing Group, 2025-07-28) Santamaría-Santiago, Ana; Sobrino, Verónica; Luna-Ramírez, Luis; López Barneo, José; Pardal Redondo, Ricardo; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS); Ministerio de Ciencia e Innovación (MICIN). España; Ministerio de Ciencia, Innovación y Universidades (MICIU). España
Adaptive homeostatic responses to oxygen (O2) deficiency (hypoxia) are essential for survival. The prototypical acute O2-sensing organ is the carotid body (CB), a neural crest-derived tissue with chemoreceptor glomus cells that express hypoxia-inhibited K+ channels. This, in turn, leads to neurotransmitter release and the activation of nerve fibers terminating in the brainstem, evoking hyperventilation. The adult CB contains a population of multipotent stem cells capable of proliferating and differentiating into new chemoreceptor cells, supporting its growth during acclimatization to chronic hypoxia. The responsiveness of glomus cells to hypoxia relies on the constitutive expression of HIF2α and a set of HIF2α-dependent genes, which define a mitochondria-to-membrane signaling pathway for acute O2 sensing. The genetic profiles of the various cell types within the CB, and how they change in response to sustained hypoxia, remain unknown. Here, we present a complete transcriptomic map of the CB, with an emphasis on the characterization of genetic profiles of the acute O2-sensing neuronal cell lineage (multipotent progenitors, neuroblasts, and mature glomus cells). Acclimatization to chronic hypoxia involves the rapid conversion of neuroblasts into mature O2-sensitive chemoreceptor cells and enhancement of the glomus cell O2-sensing and neurosecretory genetic profile.
Actin-driven nanotopography promotes stable integrin adhesion formation in developing tissue
(Springer Nature, 2024) Chen, Tianchi; Huertas Fernández-Espartero, Cecilia; Illand, Abigail; Tsai, Ching-Ting; Yang, Yang; Klapholz, Benjamin; Jouchet, Pierre; Giannone, Grégory; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
Morphogenesis requires building stable macromolecular structures from highly dynamic proteins. Muscles are anchored by long-lasting integrin adhesions to resist contractile force. However, the mechanisms governing integrin diffusion, immobilization, and activation within developing tissues remain elusive. Here, we show that actin polymerization-driven membrane protrusions form nanotopographies that enable strong adhesion at Drosophila muscle attachment sites (MASs). Super-resolution microscopy reveals that integrins assemble adhesive belts around Arp2/3-dependent actin protrusions, forming invadosome-like structures with membrane nanotopographies. Single protein tracking shows that, during MAS development, integrins become immobile and confined within diffusion traps formed by the membrane nanotopographies. Actin filaments also display restricted motion and confinement, indicating strong mechanical connection with integrins. Using isolated muscle cells, we show that substrate nanotopography, rather than rigidity, drives adhesion maturation by regulating actin protrusion, integrin diffusion and immobilization. These results thus demonstrate that actin-polymerization-driven membrane protrusions are essential for the formation of strong integrin adhesions sites in the developing embryo, and highlight the important contribution of geometry to morphogenesis.
ComBatLS: A Location- and Scale-Preserving Method for Multi-Site Image Harmonization
(Wiley, 2025-06-11) Gardner, Margaret; Shinohara , Russell T.; Bethlehem , Richard A. I.; Romero García, Rafael; Warrier, Varun; Chen, Andrew A.; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS); Junta de Andalucía; Agencia Estatal de Investigación. España
Recent study has leveraged massive datasets and advanced harmonization methods to construct normative models of neuroanatomical features and benchmark individuals' morphology. However, current harmonization tools do not preserve the effects of biological covariates including sex and age on features' variances; this failure may induce error in normative scores, particularly when such factors are distributed unequally across sites. Here, we introduce a new extension of the popular ComBat harmonization method, ComBatLS, that preserves biological variance in features' locations and scales. We use UK Biobank data to show that ComBatLS robustly replicates individuals' normative scores better than other ComBat methods when subjects are assigned to sex-imbalanced synthetic “sites.” Additionally, we demonstrate that ComBatLS significantly reduces sex biases in normative scores compared to traditional methods. Finally, we show that ComBatLS successfully harmonizes consortium data collected across over 50 studies. R implementation of ComBatLS is available at https://github.com/andy1764/ComBatFamily.
Bone marrow mesenchymal stromal cells support translation in refractory acute myeloid leukemia
(Cell Press, 2025-01-28) Lisi-Vega, Livia E.; Pievani, Alice; García-Fernández, María; Forte, Dorian; Williams, Tim L.; Serafini, Marta; Méndez-Ferrer, Simón; Fisiología Médica y Biofísica; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Cancer Research (UK); UKRI Medical Research Council
In acute myeloid leukemia (AML), malignant cells surviving chemotherapy rely on high mRNA translation and their microenvironmental metabolic support to drive relapse. However, the role of translational reprogramming in the niche is unclear. Here, we found that relapsing AML cells increase translation in their bone marrow (BM) niches, where BM mesenchymal stromal cells (BMSCs) become a source of eIF4A-cap-dependent translation machinery that is transferred to AML cells via extracellular vesicles (EVs) to meet their translational demands. In two independent models of highly chemo-resistant AML driven by MLL-AF9 or FLT3-ITD (internal tandem duplication) and nucleophosmin (NPMc) mutations, protein synthesis levels increase in refractory AML dependent on nestin+ BMSCs. Inhibiting cap-dependent translation in BMSCs abolishes their chemoprotective ability, while EVs from BMSCs carrying eIF4A boost AML cell translation and survival. Consequently, eIF4A inhibition synergizes with conventional chemotherapy. Together, these results suggest that AML cells rely on BMSCs to maintain an oncogenic translational program required for relapse.
Boldo leaves reduce seizures, neuroinflammation, and hemichannel activity in a murine model of chronic epilepsy
(BMC, 2025-12-07) Garcia Rodriguez, Claudia; Flores-Muñoz, Carolina; Fernández, Paola; Escobar, Marcela; Ardiles, Álvaro O.; Cardenas, Ana M.; Sáez, Juan C.; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
Epilepsy is a chronic neurological disorder characterized by a propensity for seizures due to an imbalance between excitatory and inhibitory brain activity. This condition also induces neuroinflammation, which contributes to disease progression. Given that hemichannels (HCs) permeabilize the cell membrane of glia playing a critical role in neuroinflammation, we investigated the antiepileptic potential of Boldo (Peumus boldus M.), an endemic Chilean tree containing several bioactive molecules including boldine, a HC inhibitor. Mice were treated with pulverized Boldo leaves, the antiseizure medication valproate, or a combination of both for 5 days. Seizure severity was assessed in a pentylenetetrazole-induced kindling mouse model. Using the dye uptake technique, we evaluated the membrane permeability in hippocampal astrocytes, microglia, and neurons. Additionally, we analyzed astroglial and microglial reactivity and measured levels of pro-inflammatory cytokines (IL-1β, IL6, and TNF-α). Both Boldo and valproate significantly reduced seizure severity. However, distinct mechanisms were observed. Valproate administration increased dye uptake in control animals and enhanced glial reactivity, corroborating its established ability to stimulate hemichannel activity. Conversely, Boldo treatment, either alone or in conjunction with valproate, reduced these parameters, consistent with its HC-blocking properties. Importantly, Boldo was more effective than valproate in reducing plasmatic levels of inflammatory and oxidative stress markers. These findings indicate that Boldo, by inhibiting these HCs, could provide a valuable therapeutic strategy to mitigate neuroinflammation in epilepsy, highlighting the clinical potential of this readily available medicinal herb.
A subset of Orai1α and Orai1β subunits heteromerizes to form CRAC channels
(BMC, 2025-06-02) Lopez, Jose J.; Jardín, Isaac; Jiménez-Velarde, Vanesa; Alvarado, Sandra; Macías-Díaz, Alvaro; Smani Hajami, Tarik; Rosado, Juan A.; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS); Ministerio de Ciencia e Innovación (MICIN). España; Ministerio de Economía. España
Background Ca2+ release-activated Ca2+ (CRAC) channels are highly Ca2+ selective plasma membrane channels formed by the hexameric assembly of Orai subunits, with a predominant role for Orai1. Two Orai1 variants have been identified, Orai1α, which comprises 301 amino acids, and a short variant, Orai1β, lacking the first N-terminal 63 or 71 amino acids; however, little is known about their possible heteromerization to form CRAC channels. Here we show that Orai1α and Orai1β exhibit different lipid raft distributions in resting cells when expressed individually, likely due to the presence of a caveolin-binding domain exclusively in Orai1α. However, when both variants are co-expressed, they show a similar distribution predominantly in the lipid raft domains, indicating potential interaction between the two Orai1 forms. Methods A lipid raft isolation protocol in combination with Western blotting assay was conducted to detect the expression of each Orai1 variants in the isolated membrane fractions. Ca2+ mobilization was determined using fura-2 and G-GECO1.2 fused to Orai1α fluorescence. Evidence of physical interaction between both Orai1 variants was provided using co-immunoprecipitation, APEX2 peroxidase-catalyzed proximity labeling, Förster resonance energy transfer (FRET) and super-resolution microscopy. Results Our results indicate that Orai1α and Orai1β exhibit different lipid raft partitioning in resting cells when expressed individually, likely attributed to the presence of a caveolin-binding domain in Orai1α. However, when both variants are co-expressed, they show a similar distribution predominantly in the lipid raft domains, indicating potential interaction between the two Orai1 forms. Expression of a dominant-negative Orai1β mutant has been found to interfere with Orai1α-mediated Ca2+ entry. Using co-immunoprecipitation, APEX2 peroxidase-catalyzed proximity labeling, Förster resonance energy transfer (FRET) and super-resolution microscopy our results indicate that there is certain interaction between Orai1α and Orai1β although both variants form mostly independent channels. Conclusions Our results indicate that while Orai1α and Orai1β mostly form separate CRAC channels, a small subset of both Orai1 variants combine to form heteromeric channels. These findings provide new insights on the nature of CRAC channels.
Influence of stromal neural crest progenitor cells on neuroblastoma radioresistance
(Taylor & Francis, 2025-01) Huertas Castaño, Carlos; Martínez López, Laura; Cabrera Roldán, Patricia; Pastor Carrillo, Nuria María; Mateos Pérez, Juan Carlos; Mateos Cordero, Santiago; Pardal Redondo, Ricardo; Domínguez García, Inmaculada; Orta Vázquez, Manuel Luis; Biología Celular; Fisiología Médica y Biofísica
Purpose A substantial proportion of children with high risk Neuroblastoma die within the first 5 years post-diagnosis despite the complex treatment applied. In the recent years, tumor environment has been revealed as key factor for cancer treatment efficacy. In this sense, non-tumorigenic Neural Crest progenitor cells from high risk patients, have been described as part of Neuroblastoma stroma, promoting tumor growth and contributing to mesenchyme formation. In this paper we wanted to study the radiobiological behavior of these cells (NB14t) and how they influence the growth of tumorigenic neuroblasts after radiotherapy. Materials and methods To achieve our aim, we employed a wide list of methods either using NB14t cells as well as commercial NB cells. We have analyzed viability, survival, cell cyle profiles and differentiation. In addition, cocultured experiments were performed to monitor the influence of stroma cells to tumorigenic neuroblasts. Results We found that stromal progenitor cells showed an extraordinary radio-resistance either cultured in attached or suspension conditions. In good agreement, we found an enhanced repair of irradiation-induced DNA lesions as compared with commercial cell lines. In addition, according to our data these cells differentiate into a Cancer Associated Fibroblasts (CAFs)-like phenotype, hence contributing to the formation of mesenchymal stroma enhancing the growth of tumor cells after irradiation. Conclusion Our data show that neural progenitor cells from high risk NB stroma are radio-resistant and promote cancer growth after irradiation. This paper can help to understand the complex cell relationships within a tumor that will determine patient prognosis after radiotherapy.
Enhanced non-enzymatic H2S generation extends lifespan and healthspan in male mice
(Elsevier, 2025-12-19) Cáliz-Molina, María Ángeles; López-Fernández-Sobrino, Raúl; Pino-Pérez, Inmaculada; Panadero-Morón, Concepción; Vilches-Pérez, María del Carmen; Camacho-Cabrera, María; García-Ruiz, Almudena; Pérez-Rosendo, Leopoldo; Espadas, Isabel; Venegas Calerón, Mónica; Aroca Aguilar, Ángeles; González Prieto, Román; Bernabeu Wittel, Máximo; Martín-Montalvo, Alejandro; Fisiología Médica y Biofísica; Bioquímica Vegetal y Biología Molecular; Biología Celular; Medicina; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía; Sociedad Española de Diabetes (SED); Instituto de Salud Carlos III
Hydrogen sulfide is a gasotransmitter with biological functions, including roles in antioxidant defenses, mitochondrial bioenergetics, and cellular signaling via cysteine persulfidation. Several longevity-promoting interventions enhance endogenous hydrogen sulfide generation. However, whether enhanced hydrogen sulfide generation extends healthspan and lifespan in mammals remains unknown. Here, we investigated the in vivo effects of the non-enzymatic hydrogen sulfide generation promoted by natural diallyl sulforated compounds. Diallyl sulforated compounds extended lifespan and improved the main aspects of healthspan, including glucoregulation, locomotor function, and neurocognition in wild-type male mice across their lifespan. At the histological and molecular levels, we observed reductions in hepatic lipid-droplet size, attenuation of transcriptional and proteomic signatures associated with mTOR and immune-related pathways, and increased cysteine persulfidation in proteins. In humans, greater protein persulfidation in individuals with polypathological conditions was associated with increased muscle strength and lower triglyceride levels, supporting its physiological relevance. Our findings uncover the potential of enhanced hydrogen sulfide generation to promote healthy aging.
Structural similarity networks reveal brain vulnerability in dementia
(Wiley, 2025-12) Montagnese, Marcella; Ebneabbasi, Amir; García-San-Martín, Natalia; Pecci-Terroba, Clara; Romero García, Rafael; Morgan, Sarah E.; Cole, James H.; Seidlitz, Jakob; Rittman, Timothy; Bethlehem, Richard A.I.; Fisiología Médica y Biofísica; CTS1086: Psiquiatría Traslacional
Introduction: Alzheimer's disease (AD) is characterized by inter-individual heterogeneity in brain degeneration, limiting diagnostic and prognostic precision. We present a novel framework integrating Morphometric Inverse Divergence (MIND) networks with hierarchical Bayesian large-scale population modeling to identify individual-level neuroanatomical deviations. Methods: MIND networks quantify similarity between brain regions using multivariate magnetic resonance imaging (MRI) features. A normative model of regional MIND values trained on UK Biobank (N = 35,133) was applied to the National Alzheimer's Coordinating Center cohort (N = 3,567). We examined brain deviations across clinical stages, apolipoprotein E (APOE) genotypes, mortality risk, and neuropathological burden. Results: Negative deviations (reduced MIND) stratified disease stages (p < 0.01) and were concentrated in specific functional networks in AD. Greater negative deviations characterized APOE ε4 homozygotes and correlated with post mortem neuropathological severity (p = 0.032). Spatially, deviation patterns were associated with maps of neurotransmitter receptor density. Discussion: This population neuroimaging modeling enables individualized brain mapping with direct utility for diagnosis, prognosis, and understanding of biological mechanisms.
Medication and atypical brain maturation in psychosis associated with long-term cognitive decline and symptom progression
(Royal college of psychiatrists; Cambridge univ press, 2025-12-11) Alemán Morillo, C.; García-San-Martín, Natalia; Bethlehem, Richard A. I.; Dorfschmidt, Lena; Alemany-Navarro, María; Segura, Patricia; Romero García, Rafael; Fisiología Médica y Biofísica; TIC245: Topological Pattern Analysis, Recognition and Learning; CTS1086: Psiquiatría Traslacional
Background Clinical progression during psychosis has been closely associated with grey matter abnormalities resulting from atypical brain development. However, the complex interplay between psychopathology and heterogeneous maturational trajectories challenges the identification of neuroanatomical features that anticipate symptomatic decline. Aims To investigate cortical volume longitudinal deviations in first-episode psychosis (FEP) using normative modelling, exploring their relationship with long-term cognitive and symptomatic outcomes, as well as their cytoarchitectural and neurobiological underpinnings. Method We collected magnetic resonance imaging (MRI), cognitive and symptomatic data from 195 healthy controls and 357 drug-naïve or minimally medicated FEP individuals that were followed up 1, 3, 5 and 10 years following the first episode (1209 MRI scans and assessments in total). Using normative modelling, we derived subject-specific centile scores for cortical volume to investigate atypical deviations in FEP and their relationship to long-term cognitive and symptomatic deterioration. The resulting centile association maps were further characterised by examining their cytoarchitectural and neurobiological attributes using normative atlases. Results FEP centiles demonstrated a widespread reduction at treatment initiation, with longitudinal analysis showing an increase during treatment time, indicating convergence towards normal maturation trajectories. Interestingly, this effect was reduced in highly medicated individuals. Additionally, we found that cognitive impairments experienced during early FEP stages worsened under long-term medication. Positive symptomatology was negatively associated with regional centiles, and individuals with higher centiles benefited most from treatment. Cytoarchitectural and neurobiological analyses revealed that regional centiles related to FEP, as well as to symptomatology, were associated with specific molecular features, such as regional serotonin and dopamine receptor densities. Conclusions Collectively, these findings underscore the potential use of centile-based normative modelling for a better understanding of how atypical cortical development contributes to the long-term clinical progression of neurodevelopmental conditions.
Dexamethasone-induced upregulation of CaV3.2 T-type Ca2+ channels in rat cardiac Myocytes
(Pergamon-Elsevier science ltd, 2018-04) Falcón Boyano, Débora; González-Montelongo, R.; Sánchez de Rojas-de Pedro, E.; Ordóñez Fernández, José Antonio; Ureña López, Juan; Castellano Orozco, Antonio Gonzalo; Fisiología Médica y Biofísica; Cirugía; Instituto de Biomedicina de Sevilla (IBIS); Consejeria de Innovacion y Ciencia de la Junta de Andalucia; Red de Investigación Cardiovascular, Ministerio de Economía y Competitividad, ISCIII; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Ministerio de Economia y Competitividad; Universidad de Sevilla; CTS1134: Investigación Traslacional en la Fisiopatología Cardiovascular; CTS591: FisioPatología Molecular del Sistema Cardiovascular
Glucocorticoids are widely used to treat acute and chronic diseases. Unfortunately, their therapeutic use is associated with severe side effects. Glucocorticoids are known to regulate several ion channels in cardiac myocytes, including voltage-dependent Ca2+ channels. Low-voltage-activated T-type Ca2+ channels are expressed in ventricular myocytes during the fetal and perinatal period, but are practically absent in the adult. However, these channels can be re-expressed in adult cardiomyocytes under some pathological conditions. We have investigated the glucocorticoid regulation of T-type Ca2+ channels in rat cardiomyocytes. Molecular studies revealed that dexamethasone induces the upregulation of CaV3.2 mRNA in neonatal rat ventricular myocytes, whereas CaV3.1 mRNA is only slightly affected. Patch-clamp recordings confirmed that T-type Ca2+ channel currents were upregulated in dexamethasone treated cardiomyocytes, and the addition of 50 μmol/L NiCl2 demonstrated that the CaV3.2 channel is responsible for this upregulation. The effect of dexamethasone on CaV3.2 is mediated by the activation and translocation to the cell nucleus of the glucocorticoid receptor (GR). We have isolated the upstream promoter of the Cacna1h gene and tested its activity in transfected ventricular myocytes. The initial in silico analysis of Cacna1h promoter revealed putative glucocorticoid response elements (GREs). Transcriptional activity assays combined with deletion analyses and chromatin immunoprecipitation assays demonstrated that GR binds to a region a GRE located in -1006/-985 bp of Cacna1h promoter. Importantly, upregulation of the CaV3.2 channel is also observed in vitro in adult rat ventricular myocytes, and in vivo in a rat model of excess of glucocorticoids.
Hypoxic induction of T-type Ca2+ channels in rat cardiac myocytes: role of HIF-1 and RhoA/ROCK signalling
(Wiley, 2015-09-01) González Rodríguez, Patricia; Falcón Boyano, Débora; Castro, M. J.; Ureña López, Juan; López Barneo, José; Castellano Orozco, Antonio Gonzalo; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS); Red RIC del Ministerio de Sanidad español; Beca BEFI del Ministerio de Sanidad español; Proyecto de Excelencia de Consejería de Innovación y Ciencia de la Junta de Andalucía; CTS1134: Investigación Traslacional en la Fisiopatología Cardiovascular; CTS516: Fisiología Celular y Biofísica; CTS591: FisioPatología Molecular del Sistema Cardiovascular
T-type Ca(2+) channels are expressed in the ventricular myocytes of the fetal and perinatal heart, but are normally downregulated as development progresses. Interestingly, however, these channels are re-expressed in adult cardiomyocytes under pathological conditions. We investigated low voltage-activated T-type Ca(2+) channel regulation in hypoxia in rat cardiomyocytes. Molecular studies revealed that hypoxia induces the upregulation of Cav 3.2 mRNA, whereas Cav 3.1 mRNA is not significantly altered. The effect of hypoxia on Cav 3.2 mRNA was time- and dose-dependent, and required hypoxia inducible factor-1α (HIF-1α) stabilization. Patch-clamp recordings confirmed that T-type Ca(2+) channel currents were upregulated in hypoxic conditions, and the addition of 50 μm NiCl2 (a T-type channel blocker) demonstrated that the Cav 3.2 channel is responsible for this upregulation. This increase in current density was not accompanied by significant changes in the Cav 3.2 channel electrophysiological properties. The small monomeric G-protein RhoA and its effector Rho-associated kinase I (ROCKI), which are known to play important roles in cardiovascular physiology, were also upregulated in neonatal rat ventricular myocytes subjected to hypoxia. Pharmacological experiments indicated that both proteins were involved in the observed upregulation of the Cav 3.2 channel and the stabilization of HIF-1α that occurred in response to hypoxia. These results suggest a possible role for Cav 3.2 channels in the increased probability of developing arrhythmias observed in ischaemic situations, and in the pathogenesis of diseases associated with hypoxic Ca(2+) overload.
Cajal’s organization of neuronal nucleus revisited
(Frontiers Media, S. A., 2025-12-03) Lafarga, Miguel; Berciano, María T.; Oriol Narcís, J.; Calvo Baltanás, Fernando; Tapia, Olga; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS); Ministerio de Ciencia e Innovación (MICIN). España; CTS007: Fisiopatología de Células Madre Neurales
In 1906, Cajal was awarded the Nobel Prize in Physiology or Medicine for his pioneering studies on the structure and organization of nerve centers. Notably, in 1910, Cajal published a seminal work in which he described the essential components of the neuronal nucleus, primarily using his reduced silver nitrate procedure. Using modern microscopy techniques, we have identified the current equivalents of the structures originally described by Cajal. These include the “fibrillar center–dense fibrillar component units” of the nucleolus, “nuclear speckles,” “transcription factories,” and “the Cajal body.” Importantly, these structures represent key nuclear compartments involved in the transcription of rDNA and protein-coding genes, pre-rRNA and pre-mRNA processing and spatial genome organization. Most of the nuclear components described by Cajal are now recognized as dynamic “nuclear condensates” assembled through liquid–liquid phase separation mechanisms that depend on various categories of RNA and RNA-binding proteins.

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