Artículos (Fisiología Médica y Biofísica)
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Artículo SMN Is Physiologically Downregulated at Wild-Type Motor Nerve Terminals but Aggregates Together with Neurofilaments in SMA Mouse Models(MDPI, 2022-10-20) Franco-Espin, Julio; Gatius, Alaó; Armengol, José Ángel; Arumugam, Saravanan; Moradi, Mehri; Sendtner, Michael; Calderó, Jordi; Tabares, Lucía; Fisiología Médica y Biofísica; Agencia Estatal de Investigación. España; Ministerio de Ciencia e Innovación (MICIN). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Deutsche Forschungsgemeinschaft / German Research Foundation (DFG); Marató de TV3 FoundationSurvival motor neuron (SMN) is an essential and ubiquitously expressed protein that participates in several aspects of RNA metabolism. SMN deficiency causes a devastating motor neuron disease called spinal muscular atrophy (SMA). SMN forms the core of a protein complex localized at the cytoplasm and nuclear gems and that catalyzes spliceosomal snRNP particle synthesis. In cultured motor neurons, SMN is also present in dendrites and axons, and forms part of the ribonucleoprotein transport granules implicated in mRNA trafficking and local translation. Nevertheless, the distribution, regulation, and role of SMN at the axons and presynaptic motor terminals in vivo are still unclear. By using conventional confocal microscopy and STED super-resolution nanoscopy, we found that SMN appears in the form of granules distributed along motor axons at nerve terminals. Our fluorescence in situ hybridization and electron microscopy studies also confirmed the presence of β-actin mRNA, ribosomes, and polysomes in the presynaptic motor terminal, key elements of the protein synthesis machinery involved in local translation in this compartment. SMN granules co-localize with the microtubule-associated protein 1B (MAP1B) and neurofilaments, suggesting that the cytoskeleton participates in transporting and positioning the granules. We also found that, while SMN granules are physiologically downregulated at the presynaptic element during the period of postnatal maturation in wild-type (non-transgenic) mice, they accumulate in areas of neurofilament aggregation in SMA mice, suggesting that the high expression of SMN at the NMJ, together with the cytoskeletal defects, contribute to impairing the bi-directional traffic of proteins and organelles between the axon and the presynaptic terminal.Artículo Role of Group I Metabotropic Glutamate Receptors in Spike Timing-Dependent Plasticity(MDPI, 2022-07-15) Martínez-Gallego, Irene; Rodríguez-Moreno, Antonio; Andrade-Talavera, Yuniesky; Fisiología Médica y Biofísica; Agencia Estatal de Investigacion; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de AndalucíaMetabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors that exhibit enormous diversity in their expression patterns, sequence homology, pharmacology, biophysical properties and signaling pathways in the brain. In general, mGluRs modulate different traits of neuronal physiology, including excitability and plasticity processes. Particularly, group I mGluRs located at the pre- or postsynaptic compartments are involved in spike timing-dependent plasticity (STDP) at hippocampal and neocortical synapses. Their roles of participating in the underlying mechanisms for detection of activity coincidence in STDP induction are debated, and diverse findings support models involving mGluRs in STDP forms in which NMDARs do not operate as classical postsynaptic coincidence detectors. Here, we briefly review the involvement of group I mGluRs in STDP and their possible role as coincidence detectors.Artículo Genetic divergence and demography of pudu deer (Pudu puda) in five provinces of southern Chile, analyzed through latitudinal and longitudinal ranges(Pensoft Publishers, 2022-06-21) Colihueque, Nelson; Cabello, Javier; Fuentes Moliz, Andrea; Fisiología Médica y Biofísica; Direccion de Investigacion of the Universidad de Los LagosPudu deer (Pudu puda) is endemic to the temperate rainforests of Chile. Genetic studies at different geographic scales for this species are required to better determine the genetic divergence within and among populations and their demography across the distribution range. These data can provide unique insights into the species or population status for conservation plans and decision-makers. We analyzed the mtDNA control region (CR) and cytochrome b (Cyt b) sequences of pudu deer in five provinces of southern Chile located at different latitudinal locations (Cautín, Valdivia, Osorno, Llanquihue and Chiloé Island) and three geographic areas within the studied provinces, representative of different longitudinal sites (Andes range, Central Valley and Coastal Range), to understand their genetic divergence and demography. The haplotype (H) and nucleotide (Π) diversities of CR and Cyt b ranged from 0.64286 to 0.98333 and from 0.00575 to 0.01022, respectively. CR diversity was significantly different among provinces, with Valdivia showing higher values than Llanquihue and Chiloé Island (H = 0.98333 vs. 0.64286–0.92727, P < 0.05). Cyt b variation also showed significant differences among provinces, particularly, among Cautín and Llanquihue (H = 1.000 vs. 0.222, P < 0.05). Genetic structuring among provinces was relatively high, as indicated by the FST index (FST = 0.41905). Clustering analysis indicated the presence of a distinctive cluster for Chiloé Island individuals. Fu’s FS and Tajima’s D based on CR revealed significant, negative deviations from equilibrium for Chiloé Island (D = -1.65898), Valdivia (Fs = -7.75335) and Llanquihue (Fs = -3.93267), suggesting population expansion in these provinces. Analysis at the longitudinal range showed significant differences among areas based on Π (P < 0.05), with the Andes range and Central Valley showing higher diversity than the Coastal Range. Neither population structuring (FST = 0.01360, P > 0.05) nor distinctive clusters in the longitudinal range were observed. Fu’s Fs and Tajima’s D were negative and significant for the Coastal Range based on CR (Fs = -6.64752, P < 0.001) and Cyt b (D = -1.74110, P < 0.05), suggesting the existence of population expansion. Our results suggest that pudu deer in the analyzed provinces is a genetically structured species, which could be associated with reduced panmixia among populations. The genetic divergence pattern and the population expansion recorded are likely to be associated with past processes of recolonization after Pleistocene glaciation events.Artículo Electroactive calcium-alginate/polycaprolactone/reduced graphene oxide nanohybrid hydrogels for skeletal muscle tissue engineering(Elsevier Science, 2022-03-11) Aparicio-Collado, J.L.; García-San-Martín, Natalia; Molina-Mateo, J.; Torregrosa Cabanilles, C.; Torregrosa Cabanilles, C.; Donderis Quiles , V.; Serrano-Aroca, A.; Sabater i Serra, R; Fisiología Médica y Biofísica; Ministerio de Ciencia e Innovación (MICIN). España; Instituto de Salud Carlos III; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)Graphene derivatives such as reduced graphene oxide (rGO) are used as components of novel biomaterials for their unique electrical properties. Electrical conductivity is a crucial factor for muscle cells, which are electrically active. This study reports the development of a new type of semi-interpenetrated polymer network based on two biodegradable FDA-approved biomaterials, sodium alginate (SA) and polycaprolactone (PCL), with Ca2+ ions as SA crosslinker. Several drawbacks such as the low cell adhesion of SA and weak structural stability can be improved with the incorporation of PCL. Furthermore, this study demonstrates how this semi-IPN can be engineered with rGO nanosheets (0.5% and 2% wt/wt rGO nanosheets) to produce electroactive nanohybrid composite biomaterials. The study focuses on the microstructure and the enhancement of physical and biological properties of these advanced materials, including water sorption, surface wettability, thermal behavior and thermal degradation, mechanical properties, electrical conductivity, cell adhesion and myogenic differentiation. The results suggest the formation of a complex nano-network with different interactions between the components: bonds between SA chains induced by Ca2+ ions (egg-box model), links between rGO nanosheets and SA chains as well as between rGO nanosheets themselves through Ca2+ ions, and strong hydrogen bonding between rGO nanosheets and SA chains. The incorporation of rGO significantly increases the electrical conductivity of the nanohybrid hydrogels, with values in the range of muscle tissue. In vitro cultures with C2C12 murine myoblasts revealed that the conductive nanohybrid hydrogels are not cytotoxic and can greatly enhance myoblast adhesion and myogenic differentiation. These results indicate that these novel electroactive nanohybrid hydrogels have great potential for biomedical applications related to the regeneration of electroactive tissues, particularly in skeletal muscle tissue engineeRINGArtículo Ca2+ channels couple spiking to mitochondrial metabolism in substantia nigra dopaminergic neurons(American Association for the Advancement of Science, 2022-09-30) Zampese, Enrico; Wokosin, David L.; González Rodríguez, Patricia; Guzman, Jaime N.; Tkatch, Tatiana; Kondapalli, Jyothisri; Surmeier, James; Fisiología Médica y Biofísica; Aligning Science Across Parkinson through the Michael J. Fox Foundation for Parkinson's Research (MJFF); JPB Foundation; Michael J. Fox Foundation; NIHHow do neurons match generation of adenosine triphosphate by mitochondria to the bioenergetic demands of regenerative activity? Although the subject of speculation, this coupling is still poorly understood, particularly in neurons that are tonically active. To help fill this gap, pacemaking substantia nigra dopaminergic neurons were studied using a combination of optical, electrophysiological, and molecular approaches. In these neurons, spike-activated calcium (Ca2+) entry through Cav1 channels triggered Ca2+ release from the endoplasmic reticulum, which stimulated mitochondrial oxidative phosphorylation through two complementary Ca2+-dependent mechanisms: one mediated by the mitochondrial uniporter and another by the malate-aspartate shuttle. Disrupting either mechanism impaired the ability of dopaminergic neurons to sustain spike activity. While this feedforward control helps dopaminergic neurons meet the bioenergetic demands associated with sustained spiking, it is also responsible for their elevated oxidant stress and possibly to their decline with aging and disease.Artículo Tumour-infiltrated cortex participates in large-scale cognitive circuits(Tipografica Varese, 2024-01) Mandal, Ayan S.; Wiener, Chemda; Assem, Moataz; Romero García, Rafael; Coelho, Pedro; McDonald, Alexa; Erez, Yaara; Fisiología Médica y Biofísica; Brain Tumour Charity; Gates Cambridge Trust; Medical Research Council; National Institute for Health Research (NIHR, UK); Royal SocietyThe extent to which tumour-infiltrated brain tissue contributes to cognitive function remains unclear. We tested the hypothesis that cortical tissue infiltrated by diffuse gliomas participates in large-scale cognitive circuits using a unique combination of intracranial electrocorticography (ECoG) and resting-state functional magnetic resonance (fMRI) imaging in four patients. We also assessed the relationship between functional connectivity with tumour-infiltrated tissue and long-term cognitive outcomes in a larger, overlapping cohort of 17 patients. We observed significant task-related high gamma (70–250 Hz) power modulations in tumour-infiltrated cortex in response to increased cognitive effort (i.e., switch counting compared to simple counting), implying preserved functionality of neoplastic tissue for complex tasks probing executive function. We found that tumour locations corresponding to task-responsive electrodes exhibited functional connectivity patterns that significantly co-localised with canonical brain networks implicated in executive function. Specifically, we discovered that tumour-infiltrated cortex with larger task-related high gamma power modulations tended to be more functionally connected to the dorsal attention network (DAN). Finally, we demonstrated that tumour-DAN connectivity is evident across a larger cohort of patients with gliomas and that it relates to long-term postsurgical outcomes in goal-directed attention. Overall, this study contributes convergent fMRI-ECoG evidence that tumour-infiltrated cortex participates in large-scale neurocognitive circuits that support executive function in health. These findings underscore the potential clinical utility of mapping large-scale connectivity of tumour-infiltrated tissue in the care of patients with diffuse gliomas.Artículo Critical requirement of SOS1 for tumor development and microenvironment modulation in KRASG12D-driven lung adenocarcinoma(Nature Publishing Group, 2023-09-20) Baltanás, Fernando; Garcia-Navas, Rósula; Rodríguez-Ramos, Pablo; Calzada, Nuria; Cuesta, Cristina; Borrajo, Javier; Fuentes-Mateos, Rocío; Olarte-San Juan, Andrea; Vidana, Nerea; Castellano, Esther; Santos, Eugenio; Fisiología Médica y Biofísica; AECC Excellence program Stop Ras Cancers; Areces Foundation; Eugenio Rodriguez Pascual Foundation; ISCIII-CIBERONC; ISCIII-MCUI; JCyL; Programa de Apoyo a Planes Estrategicos de Investigacion de Estructuras de Investigacion de Excelencia of Castilla y Leon autonomous government; Solorzano-Barruso FoundationThe impact of genetic ablation of SOS1 or SOS2 is evaluated in a murine model of KRASG12D-driven lung adenocarcinoma (LUAD). SOS2 ablation shows some protection during early stages but only SOS1 ablation causes significant, specific long term increase of survival/lifespan of the KRASG12D mice associated to markedly reduced tumor burden and reduced populations of cancer-associated fibroblasts, macrophages and T-lymphocytes in the lung tumor microenvironment (TME). SOS1 ablation also causes specific shrinkage and regression of LUAD tumoral masses and components of the TME in pre-established KRASG12D LUAD tumors. The critical requirement of SOS1 for KRASG12D-driven LUAD is further confirmed by means of intravenous tail injection of KRASG12D tumor cells into SOS1KO/KRASWT mice, or of SOS1-less, KRASG12D tumor cells into wildtype mice. In silico analyses of human lung cancer databases support also the dominant role of SOS1 regarding tumor development and survival in LUAD patients. Our data indicate that SOS1 is critically required for development of KRASG12D-driven LUAD and confirm the validity of this RAS-GEF activator as an actionable therapeutic target in KRAS mutant LUAD.Artículo miRNA-132/212 Deficiency Disrupts Selective Corticosterone Modulation of Dorsal vs. Ventral Hippocampal Metaplasticity(Molecular Diversity Preservation International, 2023-05-31) Kouhnavardi, Shima; Cabatic, Maureen; Manas-Padilla, M. Carmen; Malabanan, Marife-Astrid; Smani Hajami, Tarik; Cicvaric, Ana; Monje, Francisco J.; Fisiología Médica y Biofísica; FWF Austrian Science FundCortisol is a potent human steroid hormone that plays key roles in the central nervous system, influencing processes such as brain neuronal synaptic plasticity and regulating the expression of emotional and behavioral responses. The relevance of cortisol stands out in the disease, as its dysregulation is associated with debilitating conditions such as Alzheimer’s Disease, chronic stress, anxiety and depression. Among other brain regions, cortisol importantly influences the function of the hippocampus, a structure central for memory and emotional information processing. The mechanisms fine-tuning the different synaptic responses of the hippocampus to steroid hormone signaling remain, however, poorly understood. Using ex vivo electrophysiology and wild type (WT) and miR-132/miR-212 microRNAs knockout (miRNA-132/212−/−) mice, we examined the effects of corticosterone (the rodent’s equivalent to cortisol in humans) on the synaptic properties of the dorsal and ventral hippocampus. In WT mice, corticosterone predominantly inhibited metaplasticity in the dorsal WT hippocampi, whereas it significantly dysregulated both synaptic transmission and metaplasticity at dorsal and ventral regions of miR–132/212−/− hippocampi. Western blotting further revealed significantly augmented levels of endogenous CREB and a significant CREB reduction in response to corticosterone only in miR–132/212−/− hippocampi. Sirt1 levels were also endogenously enhanced in the miR–132/212−/− hippocampi but unaltered by corticosterone, whereas the levels of phospo-MSK1 were only reduced by corticosterone in WT, not in miR–132/212−/− hippocampi. In behavioral studies using the elevated plus maze, miRNA-132/212−/− mice further showed reduced anxiety-like behavior. These observations propose miRNA-132/212 as potential region-selective regulators of the effects of steroid hormones on hippocampal functions, thus likely fine-tuning hippocampus-dependent memory and emotional processing.Artículo Intra-operative applications of augmented reality in glioma surgery: a systematic review(Frontiers Media S.A., 2023-08-21) Ragnhildstveit, Anya; Li, Chao; Zimmerman, Mackenzie H.; Mamalakis, Michail; Curry, Victoria N.; Holle, Willis; Baig, Noor; Uğuralp, Ahmet K.; Alkhani, Layth; Oğuz-Uğuralp, Zeliha; Romero García, Rafael; Suckling, John; Fisiología Médica y Biofísica; University of Cambridge. Department of Psychiatry; NIHR Cambridge Biomedical Research CentreBackground: Augmented reality (AR) is increasingly being explored in neurosurgical practice. By visualizing patient-specific, three-dimensional (3D) models in real time, surgeons can improve their spatial understanding of complex anatomy and pathology, thereby optimizing intra-operative navigation, localization, and resection. Here, we aimed to capture applications of AR in glioma surgery, their current status and future potential. Methods: A systematic review of the literature was conducted. This adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. PubMed, Embase, and Scopus electronic databases were queried from inception to October 10, 2022. Leveraging the Population, Intervention, Comparison, Outcomes, and Study design (PICOS) framework, study eligibility was evaluated in the qualitative synthesis. Data regarding AR workflow, surgical application, and associated outcomes were then extracted. The quality of evidence was additionally examined, using hierarchical classes of evidence in neurosurgery. Results: The search returned 77 articles. Forty were subject to title and abstract screening, while 25 proceeded to full text screening. Of these, 22 articles met eligibility criteria and were included in the final review. During abstraction, studies were classified as “development” or “intervention” based on primary aims. Overall, AR was qualitatively advantageous, due to enhanced visualization of gliomas and critical structures, frequently aiding in maximal safe resection. Non-rigid applications were also useful in disclosing and compensating for intra-operative brain shift. Irrespective, there was high variance in registration methods and measurements, which considerably impacted projection accuracy. Most studies were of low-level evidence, yielding heterogeneous results. Conclusions: AR has increasing potential for glioma surgery, with capacity to positively influence the onco-functional balance. However, technical and design limitations are readily apparent. The field must consider the importance of consistency and replicability, as well as the level of evidence, to effectively converge on standard approaches that maximize patient benefit.Artículo Impaired Plakophilin-2 in obesity breaks cell cycle dynamics to breed adipocyte senescence(Nature Publishing Group, 2023-08) Lluch, Aina; Latorre, Jesicca; Serena-Maione, Angela; Espadas, Isabel; Caballano-Infantes, Estefanía; Moreno-Navarrete, José M.; Ortega, Francisco J.; Fisiología Médica y Biofísica; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation); Instituto de Salud Carlos IIIPlakophilin-2 (PKP2) is a key component of desmosomes, which, when defective, is known to promote the fibro-fatty infiltration of heart muscle. Less attention has been given to its role in adipose tissue. We report here that levels of PKP2 steadily increase during fat cell differentiation, and are compromised if adipocytes are exposed to a pro-inflammatory milieu. Accordingly, expres- sion of PKP2 in subcutaneous adipose tissue diminishes in patients with obe- sity, and normalizes upon mild-to-intense weight loss. We further show defective PKP2 in adipocytes to break cell cycle dynamics and yield premature senescence, a key rheostat for stress-induced adipose tissue dysfunction. Conversely, restoring PKP2 in inflamed adipocytes rewires E2F signaling towards the re-activation of cell cycle and decreased senescence. Our findings connect the expression of PKP2 in fat cells to the physiopathology of obesity, as well as uncover a previously unknown defect in cell cycle and adipocyte senescence due to impaired PKP2.Artículo Sulconazole inhibits PD-1 expression in immune cells and cancer cells malignant phenotype through NF-κB and calcium activity repression(Frontiers Media Sa, 2024-01-05) Pernot, Simon; Tomé, Mercedes; Galeano Otero, Isabel; Evrard, Serge; Badiola, Iker; Delom, Fedreric; Fessart, Delphine; Smani Hajami, Tarik; Khatib, Abdel-Majid; Fisiología Médica y Biofísica; La Region Nouvelle Aquitaine, Planet Vegetal, Ligue Contre le cancerThe overexpression of the immunoinhibitory receptor programmed death-1 (PD1) on T-cells is involved in immune evasion in cancer. The use of anti-PD-1/PDL-1 strategy has deeply changed the therapies of cancers and patient survival. However, their efficacy diverges greatly along with tumor type and patient populations. Thereby, novel treatments are needed to interfere with the anti-tumoral immune responses and propose an adjunct therapy. In the current study, we found that the antifungal drug Sulconazole (SCZ) inhibits PD-1 expression on activated PBMCs and T cells at the RNA and protein levels. SCZ repressed NF-κB and calcium signaling, both, involved in the induction of PD-1. Further analysis revealed cancer cells treatment with SCZ inhibited their proliferation, and migration and ability to mediate tumor growth in zebrafish embryos. SCZ found also to inhibit calcium mobilization in cancer cells. These results suggest the SCZ therapeutic potential used alone or as adjunct strategy to prevent T-cell exhaustion and promotes cancer cell malignant phenotype repression in order to improve tumor eradication.Artículo Signal peptide peptidase-like 2b modulates the amyloidogenic pathway and exhibits an Aβ-dependent expression in Alzheimer’s disease(Elsevier, 2024-03) Maccioni, Riccardo; Travisan, Caterina; Badman, Jack; Zerial, Stefania; Wagener, Annika; Andrade-Talavera, Yuniesky; Picciau, Federico; Grassi, Caterina; Chen, Gefei; Lemoine, Laetitia; Tambaro, Simone; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Academy of Finland (AKA); Ahlen-stiftelsen; Alzheimerfonden; Deutsche Forschungsgemeinschaft / German Research Foundation (DFG); DFG; Formas; Gamla tjanarinnor; Lindhes Advokatbyra Stiftelse; Olle Engkvists StiftelseAlzheimer's disease (AD) is a multifactorial disorder driven by abnormal amyloid β-peptide (Aβ) levels. In this study, we investigated the role of presenilin-like signal peptide peptidase-like 2b (SPPL2b) in AD pathophysiology and its potential as a druggable target within the Aβ cascade. Exogenous Aβ42 influenced SPPL2b expression in human cell lines and acute mouse brain slices. SPPL2b and its AD-related substrate BRI2 were evaluated in the brains of AppNL-G-F knock-in AD mice and human postmortem AD brains. An early high cortical expression of SPPL2b was observed, followed by a downregulation in late AD pathology in AppNL-G-F mice, correlating with synaptic loss. To understand the consequences of pathophysiological SPPL2b dysregulation, we found that SPPL2b overexpression significantly increased APP cleavage, while genetic deletion reduced APP cleavage and Aβ production. Notably, postmortem AD brains showed higher levels of SPPL2b's BRI2 substrate compared to healthy control samples. These results strongly support the involvement of SPPL2b in AD pathology. The early Aβ-induced upregulation of SPPL2b may enhance Aβ production in a vicious cycle, further aggravating Aβ pathology. Therefore, SPPL2b emerges as a potential anti-Aβ drug target.Artículo Mouse developmental defects, but not paraganglioma tumorigenesis, upon conditional Complex II loss in early Sox10+ cells(Wiley GOLD, 2024-07-15) Lewis, Elizabeth P.; Al Khazal, Fatimah; Wilbanks, Brandon; Gades, Naomi M.; Ortega Sáenz, Patricia; López Barneo, José; Adameyko, Igor; Maher, L. James; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; European Research Council (ERC); Ministerio de Ciencia e Innovación (MICIN). EspañaIn humans, loss of heterozygosity for defective alleles of any of the four subunits of mitochondrial tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH, also Complex II of the electron transport chain) can lead to paraganglioma tumors in neuroendocrine cells. With the goal of developing mouse models of this rare disorder, we have developed various SDH conditional loss strategies. Based on recent lineage tracing studies, we hypothesized that conditional SDHC loss in early embryogenesis during migration of primordial neural crest cells that form the susceptible chromaffin cells of the adrenal medulla might induce paraganglioma. We triggered low levels of detectable SDHC loss in Sox10+ cells at E11.5 of mouse development. We report that, rather than developing adrenal medulla paraganglioma (pheochromocytoma), offspring survived with evidence of neural crest cell dysfunction. Phenotypes included mild lower extremity gait anomalies suggestive of neural tube closure defects and patches of unpigmented fur consistent with neural crest-derived melanocyte dysfunction. These defects were not observed in mice lacking Sdhc knockout. Our results add to existing data suggesting that, unlike humans, even early embryonic (Sox10-driven) SDHx loss is inadequate to trigger paraganglioma in mice of the genetic backgrounds that have been investigated. Instead, low levels of tricarboxylic acid cycle-deficient neural crest cells cause mild developmental defects in hind limb and melanocyte function. This new model may be of interest for studies of metabolism during early neural crest cell development.Artículo Inhibition of lung tumorigenesis by transient reprogramming in cancer cells(Nature Publishing Group, 2024-11-25) Pedrosa, Pablo; Zhang, Zhenguang; Nuñez-Quintela, Víctor; Macías, David; Ge, Jianfeng; Denholm, Mary; Dyas, Anna; Estevez-Souto, Valentin; Lado-Fernandez, Patricia; Gonzalez, Patricia; Muñoz-Espín, David; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Ministerio de Ciencia e Innovación (MICIN). EspañaOncogenic transformation and Oct4, Sox2, Klf4 and c-Myc (OSKM)-mediated induction of pluripotency are two independent and incompatible cellular fates. While continuous expression of OSKM can convert normal somatic cells into teratogenic pluripotent cells, it remains speculative what is the impact of transient OSKM expression in cancer cells. Here, we find that OSKM expression limits the growth of transformed lung cells by inducing apoptosis and senescence. We identify Oct4 and Klf4 as the main individual reprogramming factors responsible for this effect. Mechanistically, the induction of cell cycle inhibitor p21 downstream of the reprogramming factors acts as mediator of cell death and senescence. Using a variety of in vivo systems, including allografts, orthotopic transplantation and KRAS-driven lung cancer mouse models, we demonstrate that transient reprogramming by OSKM expression in cancer cells impairs tumor growth and reduces tumor burden. Altogether, our results show that the induction of transient reprogramming in cancer cells is antitumorigenic opening novel potential therapeutic avenues in oncology.Artículo Hydroxycitrate delays early mortality in mice and promotes muscle regeneration while inducing a rich hepatic energetic status(Willey, 2024-05-06) Espadas, Isabel; Cáliz-Molina, María Ángeles; López-Fernández-Sobrino, Raúl; Panadero-Morón, Concepción; Sola-García, Alejandro; Soriano-Navarro, Mario; Martínez-Force, Enrique; Venegas-Calerón, Mónica; Salas, Franz Martín, Joaquin J.; Martín, Franz; Martín-Montalvo, Alejandro; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía; Ministerio de Ciencia e Innovación (MICIN). España; Spanish Society of Diabetes; Consejo Superior de Investigaciones Científicas (CSIC)ATP citrate lyase (ACLY) inhibitors have the potential of modulating central processes in protein, carbohydrate, and lipid metabolism, which can have relevant physiological consequences in aging and age-related diseases. Here, we show that hepatic phospho-active ACLY correlates with overweight and Model for End-stage Liver Disease score in humans. Wild-type mice treated chronically with the ACLY inhibitor potassium hydroxycitrate exhibited delayed early mortality. In AML12 hepatocyte cultures, the ACLY inhibitors potassium hydroxycitrate, SB-204990, and bempedoic acid fostered lipid accumulation, which was also observed in the liver of healthy-fed mice treated with potassium hydroxycitrate. Analysis of soleus tissue indicated that potassium hydroxycitrate produced the modulation of wound healing processes. In vivo, potassium hydroxycitrate modulated locomotor function toward increased wire hang performance and reduced rotarod performance in healthy-fed mice, and improved locomotion in mice exposed to cardiotoxin-induced muscle atrophy. Our findings implicate ACLY and ACLY inhibitors in different aspects of aging and muscle regeneration.Artículo Human adolescent brain similarity development is different for paralimbic versus neocortical zones(National Academy of Sciences, 2024-08-09) Dorfschmidt, Lena; Váša, František; White, Simon R.; Romero García, Rafael; Kitzbichler, Manfred G.; Alexander-Bloch, Aaron F.; Cieslak, Matthew; Mehta, Kahini; Satterthwaite, Theodore D.; Bethlehem, Richard A.I.; Seidlitz, Jakob; Vértes, Petra E.; Bullmore, Edward T.; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Junta de Andalucía; Ministerio de Ciencia e Innovación (MICIN). EspañaAdolescent development of human brain structural and functional networks is increasingly recognized as fundamental to emergence of typical and atypical adult cognitive and emotional processes. We analysed multimodal magnetic resonance imaging (MRI) data collected from N 300 healthy adolescents (51%; female; 14 to 26 y) each scanned repeatedly in an accelerated longitudinal design, to provide an analyzable dataset of 469 structural scans and 448 functional MRI scans. We estimated the morphometric similarity between each possible pair of 358 cortical areas on a feature vector comprising six macro- and microstructural MRI metrics, resulting in a morphometric similarity network (MSN) for each scan. Over the course of adolescence, we found that morphometric similarity increased in paralimbic cortical areas, e.g., insula and cingulate cortex, but generally decreased in neocortical areas, and these results were replicated in an independent developmental MRI cohort (N 304). Increasing hubness of paralimbic nodes in MSNs was associated with increased strength of coupling between their morphometric similarity and functional connectivity. Decreasing hubness of neocortical nodes in MSNs was associated with reduced strength of structure–function coupling and increasingly diverse functional connections in the corresponding fMRI networks. Neocortical areas became more structurally differentiated and more functionally integrative in a metabolically expensive process linked to cortical thinning and myelination, whereas paralimbic areas specialized for affective and interoceptive functions became less differentiated, as hypothetically predicted by a developmental transition from periallocortical to proisocortical organization of the cortex. Cytoarchitectonically distinct zones of the human cortex undergo distinct neurodevelopmental programs during typical adolescence.Artículo Handshaking for ultrafast endocytosis: Dynamin1xA and Endophilin A1 sealed the deal(Nature Pub. Group, 2024-08) López-Begines, Santiago; Fernández-Chacón, Rafael; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Agencia Estatal de Investigación. EspañaBrain function relies on quick inter-neuron communication at specialized points of contact termed synapses. In the latest issue of The EMBO Journal, Imoto, Xue, et al (2024) report the discovery of a novel, regulated interaction between two major endocytosis players which supports the notion of a preassembled protein machinery at presynaptic nerve terminals that can explain how the high speed of ultrafast endocytosis is possibleArtículo Evaluating the impact of a rigid and a deformable registration method of pre-treatment images for hypoxia-based dose painting(Elsevier, 2024-05-20) Lazzeroni, M.; Ureba Sánchez, Ana María; Rosenberg, V.; Schäfer, H.; Rühle, A.; Baltas, D.; Toma-Dasu, I.; Grosu, A. L.; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Cancer Research Funds of Radiumhemmet; Swedish Research CouncilPurpose To assess the impact of rigid and deformable image registration methods (RIR, DIR) on the outcome of a hypoxia-based dose painting strategy. Materials and methods Thirty head and neck cancer patients were imaged with [18F]FMISO-PET/CT before radiotherapy. [18F]FMISO-PET/CT images were registered to the planning-CT by RIR or DIR. The [18F]FMISO uptake was converted into oxygen partial pressure (pO2) maps. Hypoxic Target Volumes were contoured on pO2 maps for the deformed (HTVdef) and non-deformed (HTV) cases. A dose escalation strategy by contours, aiming at 95 % tumour control probability (TCP), was applied. HTVs were characterised based on geometry-related metrics, the underlying pO2 distribution, and the dose boost level. A dosimetric and radiobiological evaluation of selected treatment plans made considering RIR and DIR was performed. Moreover, the TCP of the RIR dose distribution was evaluated when considering the deformed [18F]FMISO-PET image as an indicator of the actual target radiosensitivity to determine the potential impact of an unalignment. Results Statistically significant differences were found between HTV and HTVdef for volume-based metrics and underlying pO2 distribution. Eight out of nine treatment plans for HTV and HTVdef showed differences on the level 10 %/3 mm on a gamma analysis. The TCP difference, however, between RIR and the case when the RIR dose distribution was used with the deformed radiosensitivity map was below 2 pp. Conclusions Although the choice of the CTplan-to-PET registration method pre-treatment impacts the HTV localisation and morphology and the corresponding dose distribution, it negligibly affects the TCP in the proposed dose escalation strategy by contours.Artículo Disrupted sleep-wake regulation in the MCI-Park mouse model of Parkinson’s disease(Springer, 2024-03-11) Summa, K. C.; Jiang, P.; González Rodríguez, Patricia; Huang, X.; Lin, X.; Vitaterna, M. H.; Dan, Y.; Surmeier, D. J.; Turek, F. W.; Universidad de Sevilla. Departamento de Fisiología Médica y BiofísicaDisrupted sleep has a profound adverse impact on lives of Parkinson’s disease (PD) patients and their caregivers. Sleep disturbances are exceedingly common in PD, with substantial heterogeneity in type, timing, and severity. Among the most common sleep-related symptoms reported by PD patients are insomnia, excessive daytime sleepiness, and sleep fragmentation, characterized by interruptions and decreased continuity of sleep. Alterations in brain wave activity, as measured on the electroencephalogram (EEG), also occur in PD, with changes in the pattern and relative contributions of different frequency bands of the EEG spectrum to overall EEG activity in different vigilance states consistently observed. The mechanisms underlying these PD-associated sleep-wake abnormalities are poorly understood, and they are ineffectively treated by conventional PD therapies. To help fill this gap in knowledge, a new progressive model of PD – the MCI-Park mouse – was studied. Near the transition to the parkinsonian state, these mice exhibited significantly altered sleep-wake regulation, including increased wakefulness, decreased non-rapid eye movement (NREM) sleep, increased sleep fragmentation, reduced rapid eye movement (REM) sleep, and altered EEG activity patterns. These sleep-wake abnormalities resemble those identified in PD patients. Thus, this model may help elucidate the circuit mechanisms underlying sleep disruption in PD and identify targets for novel therapeutic approaches.Artículo Brain tumour microstructure is associated with post-surgical cognition(Nature Publishing Group, 2024-03-07) Aznarez-Sanado, Maite; Romero García, Rafael; Li, Chao; Morris, Rob C.; Price, Stephen J.; Manly, Thomas; Santarius, Thomas; Erez, Yaara; Hart, Michael G.; Suckling, John; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Junta de Andalucía; Cancer Research Cambridge Centre. United KingdomBrain tumour microstructure is potentially predictive of changes following treatment to cognitive functions subserved by the functional networks in which they are embedded. To test this hypothesis, intra-tumoural microstructure was quantified from diffusion-weighted MRI to identify which tumour subregions (if any) had a greater impact on participants’ cognitive recovery after surgical resection. Additionally, we studied the role of tumour microstructure in the functional interaction between the tumour and the rest of the brain. Sixteen patients (22–56 years, 7 females) with brain tumours located in or near speech-eloquent areas of the brain were included in the analyses. Two different approaches were adopted for tumour segmentation from a multishell diffusion MRI acquisition: the first used a two-dimensional four group partition of feature space, whilst the second used data-driven clustering with Gaussian mixture modelling. For each approach, we assessed the capability of tumour microstructure to predict participants’ cognitive outcomes after surgery and the strength of association between the BOLD signal of individual tumour subregions and the global BOLD signal. With both methodologies, the volumes of partially overlapped subregions within the tumour significantly predicted cognitive decline in verbal skills after surgery. We also found that these particular subregions were among those that showed greater functional interaction with the unaffected cortex. Our results indicate that tumour microstructure measured by MRI multishell diffusion is associated with cognitive recovery after surgery.