Artículos (Fisiología Médica y Biofísica)

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

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Early deviations from normative brain morphology and cortical microstructure in schizophrenia spectrum disorders
(Springer Nature, 2026-07-15) Alemán Morillo, C.; García-San-Martín, Natalia; Bethlehem, Richard A. I.; Pombo Segura, Patricia; Gómez, Chloé; Pasquini, Alessia; Salguero Quirós, Pablo; Romero García, Rafael; Fisiología Médica y Biofísica; Junta de Andalucía; ERANET Neuron; Gobierno de España; UK Medical Research Council; NIHR Cambridge Biomedical Research Centre
In schizophrenia spectrum disorders (SSD), structural alterations of the gray matter (GM) and white matter (WM) have been widely described. However, the complex interplay between early disease-related changes and ongoing brain maturation challenges our ability to identify early biomarkers. In this study, we investigated structural abnormalities and their association with symptoms in a drug-naïve or minimally medicated sample comprising 113 patients with SSD and 112 neurotypical controls. Specifically, we derived centile scores using normative modelling from cortical thickness (CT), and subcortical volumes derived from structural MRI images, and diffusion tensor imaging-derived (DTI) WM tract fractional anisotropy (FA). In addition, we derived raw cortical mean diffusivity (cMD) metrics from DTI. Compared to controls, SSD participants showed reduced CT centiles, ventricular enlargement, and subcortical centile reductions in the hippocampus, thalamus, amygdala, and nucleus accumbens. SSD was also associated with widespread increases in cMD. We also explored associations among these structural markers, identifying significant relationships between CT centiles and raw cMD, as well as between subcortical centiles and FA tract-based centiles. No interaction with SSD diagnosis was found. Furthermore, positive symptoms correlated negatively with CT and FA tract-based centiles, and showed widespread positive associations with raw cMD, whereas negative symptoms showed no associations. These findings underscore multimodal brain abnormalities that originate early in the course of SSD and their distinct associations with symptoms. Our results support the potential of both normative modelling and diffusion imaging markers to identify individualized early brain changes in SSD Among these, cMD emerges as a potential marker of SSD-related microstructural alterations.
Author Correction: Transcriptomic and cellular decoding of regional brain vulnerability to neurogenetic disorders
(Nature Publishing Group, 2020-07-03) Seidlitz, Jakob; Nadig, Ajay; Liu, Siyuan; Bethlehem, Richard A. I.; Vértes, Petra E.; Morgan, Sarah E.; Váša, František; Romero García, Rafael; Raznahan, Armin; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
Publisher Correction: Cellular adaptation to oxygen deficiency beyond the Nobel award
(Nature Publishing Group, 2020-02-25) López Barneo, José; Simón, M. Celeste; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
Corrigendum: Denatonium as a Bitter Taste Receptor Agonist Modifies Transcriptomic Profile and Functions of Acute Myeloid Leukemia Cells
(Frontiers Media Sa, 2021-04-21) Salvestrini, Valentina; Ciciarello, Marilena; Pensato, Valentina; Simonetti, Giorgia; Laginestra, Maria Antonella; Bruno, Samantha; Pazzaglia, Martina; Méndez-Ferrer, Simón; Curti, Antonio; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
Corrigendum: SARAF and Orai1 Contribute to Endothelial Cell Activation and Angiogenesis
(Frontiers Media Sa, 2021-04-20) Galeano-Otero, Isabel; Toro Estévez, Raquel del; Khatib, Abdel-Majid; Rosado, Juan Antonio; Ordóñez-Fernández, Antonio; Smani, Tarik; Fisiología Médica y Biofísica; Cirugía; Instituto de Biomedicina de Sevilla (IBIS)
Long-term consequences of adolescent methylphenidate exposure on sustained attention and prelimbic PV+ interneuron maturation in rats
(Elsevier, 2026) Pérez Colorado, Antonio; López García, Juan Carlos; Martínez Marín, Reyes; Vargas Romero, Juan Pedro; Díaz Argandoña, Estrella; Psicología Experimental; Fisiología Médica y Biofísica; Agencia Estatal de Investigación. España; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
Adolescence is a sensitive period for the maturation of prefrontal GABAergic circuitry, particularly involving parvalbumin-expressing (PV+) interneurons that regulate excitatory–inhibitory balance and support attentional control. Methylphenidate (MPH), widely prescribed for attention-deficit/hyperactivity disorder (ADHD, is commonly administered throughout adolescence, yet its long-term impact on PV+ interneuron development remains unclear. Here, we examined whether chronic MPH exposure during distinct adolescent windows (PD35–55, PD42–62, PD49–69) alters PV+ interneuron maturation in the prelimbic (PrL) cortex and produces enduring attentional impairments. Male and female Wistar rats received 5 mg/kg MPH for 20 consecutive days and, in adulthood (PD100), were tested in a sustained attention task (SAT) and its distractor variant (dSAT). MPH exposure produced a reduction in PV+ interneuron density in the PrL, but only treatment during late adolescence (PD49–69) disrupted the normal developmental increase in PV+ cells. This PV+ reduction interneurons was accompanied by persistent deficits in sustained attention, reflected by decreased hit rates and poor recovery under high attentional demand, while correct rejections remained intact. These findings identify late adolescence as a critical vulnerability window in which MPH disrupts prefrontal inhibitory maturation and is associated with altered adult attentional performance, highlighting the importance of developmental timing in psychostimulant exposure.
Temporal dynamics of substance P and its association with cytokine release syndrome after CD19 CAR-T therapy in pediatric B-ALL
(BMC; Springer Science and Business Media LLC, 2026-06-10) Molinos-Quintana, Águeda; Rodríguez Gil, Alfonso; Caballero Velázquez, Teresa; García-Guerrero, Estefanía; Alcalde-Mellado, Patricia; Hernández-Díaz, Paola; Pérez Simón, José Antonio; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS); Medicina; BIO271: Expresión Génica en Eucariontes
Background Cytokine Release Syndrome (CRS) remains a major toxicity associated with chimeric antigen receptor T (CAR-T) cell therapy, particularly in pediatric patients. Although neuroimmune mediators have been implicated in systemic inflammation, the role of neuropeptides such as Substance P (SP) in CRS has not yet been explored in this setting. Methods Plasma SP levels were measured using an enzyme-linked immunosorbent assay (ELISA) and analyzed longitudinally at predefined time points (day − 1, +7, + 14, and + 28) and during CRS when additional samples were available in 18 pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) treated with CD19 CAR-T therapy (tisagenlecleucel) in a real-world clinical setting. SP dynamics were correlated with severity of CRS, inflammatory biomarkers, and CD19 CAR-T expansion kinetics. Results Baseline SP levels were similar between patients who developed severe CRS (grade ≥ 3) and those with non-severe CRS. In contrast, the increase in SP levels from baseline (ΔSP) was significantly higher in patients who developed severe CRS (1523 pg/mL vs. 189 pg/mL, p = 0.01). A peak in SP levels was observed at the onset of severe CRS in all three patients, coinciding with the beginning of clinical toxicity and occurring shortly before the elevation in ferritin levels. In these three cases, IL-6 levels increased in close temporal proximity to the rise in SP at the time of maximum CRS severity. Overall, SP levels declined by day + 14 post-infusion, shortly after the peak of CAR-T expansion. This decline coincided temporally with the administration of anti-CRS treatment in the subset of patients with severe CRS. SP levels later increased toward the end of the observation period (around day + 28), approaching baseline values. Conclusions These findings suggest that SP dynamics may be linked to the early inflammatory response during CRS and support further investigation of the SP–NK1 receptor axis as a potential therapeutic target to modulate CD19 CAR-T–related toxicity.
Correction: Assigning the right credit to the wrong action: compulsivity in the general population is associated with augmented outcome-irrelevant value-based learning
(2021-01-02) Shahar, Nitzan; Hauser, Tobias U.; Moran, Rani; Moutoussis, Michael; Bullmore, Edward T.; Raymond, J. Dolan; NSPN Consortium; Romero García, Rafael; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
Author Correction: Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice
(Nature Publishing Group, 2022-03-25) McElroy, Gregory S.; Chakrabarty, Ram P.; D’Alessandro, Karis B.; Yuan‑Shih, Hu; Vasan, Karthik; Gao Chen, Lin; López Barneo, José; Stoolman, Joshua S.; Chandel, Navdeep S.; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
Corrigendum to “Downregulation of Thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer” [Redox Biol. 34 (2020) 101528]
(Elsevier Science Bv, 2023-07-19) González, R.; Rodríguez Hernández, María A.; Negrete, M.; Ranguelova, K.; Rossin, A.; Choya-Foces, C.; Muntané Relat, Jordi; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
Author Correction: Disrupted sleep-wake regulation in the MCI-Park mouse model of Parkinson’s disease
(Springer, 2024-07-15) Summa, KC; Jiang, P; González Rodríguez, Patricia; Huang, X; Lin, X.; Vitaterna, M. H.; Turek, F. W.; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
Correction: Sanchez-Collado et al. Orai2 Modulates Store-Operated Ca2+ Entry and Cell Cycle Progression in Breast Cancer Cells. Cancers 2021, 14, 114
(MDPI, 2023-02-17) Sánchez Collado, José; Lopez, Jose J.; Cantonero, Carlos; Jardin, Isaac; Smani Hajami, Tarik; Rosado, Juan Antonio; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
Author Correction: The impact of the initial COVID-19 outbreak on young adults’ mental health: a longitudinal study of risk and resilience factors
(Nature Publishing Group, 2025-03-24) Wiedemann, Anna; Stochl, Jan; Neufeld, Sharon A. S; Fritz, Jessica; Bhatti, Junaid; Hook, Roxanne W.; NSPN Consortium; Romero García, Rafael; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
Receptor–Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment
(MDPI, 2018-06-03) Borroto-Escuela, Dasiel O.; Narváez, Manuel; Ambrogini, Patrizia; Ferraro, Luca; Romero-Fernández, Wilber; Andrade-Talavera, Yuniesky; Fuxe, Kjell; Fisiología Médica y Biofísica; Ministerio de Economia, Industria y Competitividad (MINECO). España
Due to the binding to a number of proteins to the receptor protomers in receptor heteromers in the brain, the term “heteroreceptor complexes” was introduced. A number of serotonin 5-HT1A heteroreceptor complexes were recently found to be linked to the ascending 5-HT pathways known to have a significant role in depression. The 5-HT1A–FGFR1 heteroreceptor complexes were involved in synergistically enhancing neuroplasticity in the hippocampus and in the dorsal raphe 5-HT nerve cells. The 5-HT1A protomer significantly increased FGFR1 protomer signaling in wild-type rats. Disturbances in the 5-HT1A–FGFR1 heteroreceptor complexes in the raphe-hippocampal 5-HT system were found in a genetic rat model of depression (Flinders sensitive line (FSL) rats). Deficits in FSL rats were observed in the ability of combined FGFR1 and 5-HT1A agonist cotreatment to produce antidepressant-like effects. It may in part reflect a failure of FGFR1 treatment to uncouple the 5-HT1A postjunctional receptors and autoreceptors from the hippocampal and dorsal raphe GIRK channels, respectively. This may result in maintained inhibition of hippocampal pyramidal nerve cell and dorsal raphe 5-HT nerve cell firing. Also, 5-HT1A–5-HT2A isoreceptor complexes were recently demonstrated to exist in the hippocampus and limbic cortex. They may play a role in depression through an ability of 5-HT2A protomer signaling to inhibit the 5-HT1A protomer recognition and signaling. Finally, galanin (1–15) was reported to enhance the antidepressant effects of fluoxetine through the putative formation of GalR1–GalR2–5-HT1A heteroreceptor complexes. Taken together, these novel 5-HT1A receptor complexes offer new targets for treatment of depression.
Neuronal regulation of bone marrow stem cell niches
(F1000 Research Ltd, 2020-06-16) Méndez-Ferrer, Simón; Fielding, Claire; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
The bone marrow (BM) is the primary site of postnatal hematopoiesis and hematopoietic stem cell (HSC) maintenance. The BM HSC niche is an essential microenvironment which evolves and responds to the physiological demands of HSCs. It is responsible for orchestrating the fate of HSCs and tightly regulates the processes that occur in the BM, including self-renewal, quiescence, engraftment, and lineage differentiation. However, the BM HSC niche is disturbed following hematological stress such as hematological malignancies, ionizing radiation, and chemotherapy, causing the cellular composition to alter and remodeling to occur. Consequently, hematopoietic recovery has been the focus of many recent studies and elucidating these mechanisms has great biological and clinical relevance, namely to exploit these mechanisms as a therapeutic treatment for hematopoietic malignancies and improve regeneration following BM injury. The sympathetic nervous system innervates the BM niche and regulates the migration of HSCs in and out of the BM under steady state. However, recent studies have investigated how sympathetic innervation and signaling are dysregulated under stress and the subsequent effect they have on hematopoiesis. Here, we provide an overview of distinct BM niches and how they contribute to HSC regulatory processes with a particular focus on neuronal regulation of HSCs under steady state and stress hematopoiesis.
Cellular Heterogeneity of Mesenchymal Stem/Stromal Cells in the Bone Marrow
(Frontiers Media Sa, 2021-07-06) Yo, Mabuchi; Okawara, Chikako; Méndez-Ferrer, Simón; Akazawa, Chihiro; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS); European Union (UE). H2020
Mesenchymal stem/stromal cells (MSCs) are present in various body tissues and help in maintaining homeostasis. The stemness of MSCs has been evaluated in vitro. In addition, analyses of cell surface antigens and gene expression patterns have shown that MSCs comprise a heterogeneous population, and the diverse and complex nature of MSCs makes it difficult to identify the specific roles in diseases. There is a lack of understanding regarding the classification of MSC properties. In this review, we explore the characteristics of heterogeneous MSC populations based on their markers and gene expression profiles. We integrated the contents of previously reported single-cell analysis data to better understand the properties of mesenchymal cell populations. In addition, the cell populations involved in the development of myeloproliferative neoplasms (MPNs) are outlined. Owing to the diversity of terms used to describe MSCs, we used the text mining technology to extract topics from MSC research articles. Recent advances in technology could improve our understanding of the diversity of MSCs and help us evaluate cell populations.
The testosterone-dependent and independent transcriptional networks in the hypothalamus of Gpr54 and Kiss1 knockout male mice are not fully equivalent
(Biomed Central Ltd, 2011-04-28) Prentice, Leah M.; D'Anglemont De Tassigny, Xavier; McKinney, Steven; Ruiz de Algara, Teresa; Yap, Damian B.; Turashvili, Gulisa; Aparicio, Samuel AJ.; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
Background Humans and mice with loss of function mutations in GPR54 (KISS1R) or kisspeptin do not progress through puberty, caused by a failure to release GnRH. The transcriptional networks regulated by these proteins in the hypothalamus have yet to be explored by genome-wide methods. Results We show here, using 1 million exon mouse arrays (Exon 1.0 Affymetrix) and quantitative polymerase chain reaction (QPCR) validation to analyse microdissected hypothalamic tissue from Gpr54 and Kiss1 knockout mice, the extent of transcriptional regulation in the hypothalamus. The sensitivity to detect important transcript differences in microdissected RNA was confirmed by the observation of counter-regulation of Kiss1 expression in Gpr54 knockouts and confirmed by immunohistochemistry (IHC). Since Gpr54 and Kiss1 knockout animals are effectively pre-pubertal with low testosterone (T) levels, we also determined which of the validated transcripts were T-responsive and which varied according to genotype alone. We observed four types of transcriptional regulation (i) genotype only dependent regulation, (ii) T only dependent regulation, (iii) genotype and T-dependent regulation with interaction between these variables, (iv) genotype and T-dependent regulation with no interaction between these variables. The results implicate for the first time several transcription factors (e.g. Npas4, Esr2), proteases (Klk1b22), and the orphan 10-transmembrane transporter TMEM144 in the biology of GPR54/kisspeptin function in the hypothalamus. We show for the neuronal activity regulated transcription factor NPAS4, that distinct protein over-expression is seen in the hypothalamus and hippocampus in Gpr54 knockout mice. This links for the first time the hypothalamic-gonadal axis with this important regulator of inhibitory synapse formation. Similarly we confirm TMEM144 up-regulation in the hypothalamus by RNA in situ hybridization and western blot. Conclusions Taken together, global transcriptional profiling shows that loss of GPR54 and kisspeptin are not fully equivalent in the mouse hypothalamus.
Role of C/EBPβ Transcription Factor in Adult Hippocampal Neurogenesis
(Public Library Science, 2011-10-07) Cortes-Canteli, Marta; Aguilar Morante, Diana; Sanz-SanCristobal, Marina; Megias, Diego; Santos, Ángel; Perez-Castillo, Ana; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
Background The dentate gyrus of the hippocampus is one of the regions in which neurogenesis takes place in the adult brain. We have previously demonstrated that CCAAT/enhancer binding protein β (C/EBPβ) is expressed in the granular layer of the dentate gyrus of the adult mouse hippocampus. Taking into account the important role of C/EBPβ in the consolidation of long term memory, the fact that newborn neurons in the hippocampus contribute to learning and memory processes, and the role of this transcription factor, previously demonstrated by our group, in regulating neuronal differentiation, we speculated that this transcription factor could regulate stem/progenitor cells in this region of the brain. Methodology/Principal Findings Here, we show, using C/EBPβ knockout mice, that C/EBPβ expression is observed in the subset of newborn cells that proliferate in the hippocampus of the adult brain. Mice lacking C/EBPβ present reduced survival of newborn cells in the hippocampus, a decrease in the number of these cells that differentiate into neurons and a diminished number of cells that are proliferating in the subgranular zone of the dentate gyrus. These results were further confirmed in vitro. Neurosphere cultures from adult mice deficient in C/EBPβ present less proliferation and neuronal differentiation than neurospheres derived from wild type mice. Conclusions/Significance In summary, using in vivo and in vitro strategies, we have identified C/EBPβ as a key player in the proliferation and survival of the new neurons produced in the adult mouse hippocampus. Our results support a novel role of C/EBPβ in the processes of adult hippocampal neurogenesis, providing new insights into the mechanisms that control neurogenesis in this region of the brain.
Mll5 Is Required for Normal Spermatogenesis
(Public Library Science, 2011-10-11) Yap, Damian B.; Walker, David C.; Prentice, Leah M.; McKinney, Steven; Turashvili, Gulisa; Mooslehner-Allen, Katrin; D'Anglemont De Tassigny, Xavier; Aparicio, Samuel; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
Background Mll5 is currently a member of the Mll family of SET domain histone methyltransferase proteins but studies have also showed that it could be part of the SET3 branch of proteins. Recently, constitutive knock out animal studies have shown that Mll5 is required for proper haematopoietic stem cell differentiation, and loss of Mll5 results in synthetic lethality for genome de-methylation. Mll5 deficient male mice are infertile and here we analyse the consequences of Mll5 deficiency for spermatogenesis. Methodology/Principal Findings Mll5 deficient male mice, but not female mice, are infertile. Here we show using RNA in-situ hybridization that Mll5 is expressed in the germ cells of the testes of wild type mice. Consistent with the expression of Mll5, we demonstrate by electron microscopy, video microscopy and in vitro fertilisation techniques that Mll5 deficient mice have defects in terminal maturation and packaging of sperm. The defects seen include detachment of the acrosomal cap and impaired excess cytoplasm removal. Functional tests of sperm motility show a lack of progressive motility of spermatozoa from Mll5 deficient animals. None of these defects could be rescued by in vitro fertilization. Using microarray analysis we show that transcripts implicated in spermatogenesis are dysregulated. Conclusions/Significance Our data demonstrate a clear role of Mll5 in mammalian spermatogenesis at the level of terminal differentiation providing further support for its classification in the SET3 branch of proteins. Moreover, this study identifies Tlk2, Utx, Gpr64, Sult4a1, Rap2ip, Vstm2 and HoxA10 as possible Mll5 targets that together may account for the observed spermatozoa maturation defects.
Inotropic Action of the Puberty Hormone Kisspeptin in Rat, Mouse and Human: Cardiovascular Distribution and Characteristics of the Kisspeptin Receptor
(Public Library Science, 2011-11-22) Maguire, Janet J.; Kirby, Helen R.; Mead, Emma J.; Kuc, Rhoda E.; D'Anglemont De Tassigny, Xavier; Colledge, William H.; Davenport, Anthony P.; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS)
Kisspeptins, the ligands of the kisspeptin receptor known for its roles in reproduction and cancer, are also vasoconstrictor peptides in atherosclerosis-prone human aorta and coronary artery. The aim of this study was to further investigate the cardiovascular localisation and function of the kisspeptins and their receptor in human compared to rat and mouse heart. Immunohistochemistry and radioligand binding techniques were employed to investigate kisspeptin receptor localisation, density and pharmacological characteristics in cardiac tissues from all three species. Radioimmunoassay was used to detect kisspeptin peptide levels in human normal heart and to identify any pathological changes in myocardium from patients transplanted for cardiomyopathy or ischaemic heart disease. The cardiac function of kisspeptin receptor was studied in isolated human, rat and mouse paced atria, with a role for the receptor confirmed using mice with targeted disruption of Kiss1r. The data demonstrated that kisspeptin receptor-like immunoreactivity localised to endothelial and smooth muscle cells of intramyocardial blood vessels and to myocytes in human and rodent tissue. [125I]KP-14 bound saturably, with subnanomolar affinity to human and rodent myocardium (KD = 0.12 nM, human; KD = 0.44 nM, rat). Positive inotropic effects of kisspeptin were observed in rat, human and mouse. No response was observed in mice with targeted disruption of Kiss1r. In human heart a decrease in cardiac kisspeptin level was detected in ischaemic heart disease. Kisspeptin and its receptor are expressed in the human, rat and mouse heart and kisspeptins possess potent positive inotropic activity. The cardiovascular actions of the kisspeptins may contribute to the role of these peptides in pregnancy but the consequences of receptor activation must be considered if kisspeptin receptor agonists are developed for use in the treatment of reproductive disorders or cancer.

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