Artículos (Fisiología Médica y Biofísica)

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Two human brain systems micro-structurally associated with obesity
(Life Sciences Publications, Ltd., 2023-10-20) Kitzbichler, Manfred G.; Martins, Daniel; Bethlehem, Richard A.I.; Dear, Richard; Romero García, Rafael; Warrier, Varun; Seidlitz, Jakob; Fisiología Médica y Biofísica; Wellcome Trust; Alzheimer's Disease (NIMA) consortium; National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre (ETB); NIHR Senior Investigator award
The relationship between obesity and human brain structure is incompletely understood. Using diffusion-weighted MRI from ∼30,000 UK Biobank participants, we test the hypothesis that obesity (waist-to-hip ratio, WHR) is associated with regional differences in two micro-structural MRI metrics: isotropic volume fraction (ISOVF), an index of free water, and intra-cellular volume fraction (ICVF), an index of neurite density. We observed significant associations with obesity in two coupled but distinct brain systems: a prefrontal/temporal/striatal system associated with ISOVF and a medial temporal/occipital/striatal system associated with ICVF. The ISOVF~WHR system colocated with expression of genes enriched for innate immune functions, decreased glial density, and high mu opioid (MOR) and other neurotransmitter receptor density. Conversely, the ICVF~WHR system co-located with expression of genes enriched for G-protein coupled receptors and decreased density of MOR and other receptors. To test whether these distinct brain phenotypes might differ in terms of their underlying shared genetics or relationship to maps of the inflammatory marker C-reactive Protein (CRP), we estimated the genetic correlations between WHR and ISOVF (rg = 0.026, P = 0.36) and ICVF (rg = 0.112, P < 9×10−4) as well as comparing correlations between WHR maps and equivalent CRP maps for ISOVF and ICVF (P<0.05). These correlational results are consistent with a two-way mechanistic model whereby genetically determined differences in neurite density in the medial temporal system may contribute to obesity, whereas water content in the prefrontal system could reflect a consequence of obesity mediated by innate immune system activation.
The Ca2+ Sensor STIM in Human Diseases
(MDPI, 2023-08-22) Berna-Erro, Alejandro; Sanchez-Collado, Jose; Nieto-Felipe, Joel; Macias-Diaz, Alvaro; Redondo, Pedro C.; Smani Hajami, Tarik; Rosado, Juan A.; Fisiología Médica y Biofísica; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; Junta de Extremadura; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
The STIM family of proteins plays a crucial role in a plethora of cellular functions through the regulation of store-operated Ca2+ entry (SOCE) and, thus, intracellular calcium homeostasis. The two members of the mammalian STIM family, STIM1 and STIM2, are transmembrane proteins that act as Ca2+ sensors in the endoplasmic reticulum (ER) and, upon Ca2+ store discharge, interact with and activate the Orai/CRACs in the plasma membrane. Dysregulation of Ca2+ signaling leads to the pathogenesis of a variety of human diseases, including neurodegenerative disorders, cardiovascular diseases, cancer, and immune disorders. Therefore, understanding the mechanisms underlying Ca2+ signaling pathways is crucial for developing therapeutic strategies targeting these diseases. This review focuses on several rare conditions associated with STIM1 mutations that lead to either gain- or loss-of-function, characterized by myopathy, hematological and immunological disorders, among others, and due to abnormal activation of CRACs. In addition, we summarize the current evidence concerning STIM2 allele duplication and deletion associated with language, intellectual, and developmental delay, recurrent pulmonary infections, microcephaly, facial dimorphism, limb anomalies, hypogonadism, and congenital heart defects.
Tumour-infiltrated cortex participates in large-scale cognitive circuits
(Elsevier, 2024-01-30) Mandal, Ayan S.; Wiener, Chemda; Assem, Moataz; Romero García, Rafael; Coelho, Pedro; Erez, Yaara; Fisiología Médica y Biofísica; Gates Cambridge Trust; Medical Research Council; National Institute for Health Research (NIHR, UK); Royal Society (UK)
The 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.
Robust estimation of cortical similarity networks from brain MRI
(Nature Publishing Group, 2023-07-17) Sebenius, Isaac; Seidlitz, Jakob; Warrier, Varun; Bethlehem, Richard A.I.; Alexander-Bloch, Aaron F.; Mallard, Travis T.; Romero García, Rafael; Morgan, Sarah E.; Fisiología Médica y Biofísica; National Institute of Mental Health (NIMH); Autism Research Trust; Universidad de Sevilla; University of Cambridge; NIH; NIHR Cambridge Biomedical Research Centre; National Institute for Health and Care Research (NIHR) Senior Investigator; Junta de Andalucía
Structural similarity is a growing focus for magnetic resonance imaging (MRI) of connectomes. Here we propose Morphometric INverse Divergence (MIND), a new method to estimate within-subject similarity between cortical areas based on the divergence between their multivariate distributions of multiple MRI features. Compared to the prior approach of morphometric similarity networks (MSNs) on n > 11,000 scans spanning three human datasets and one macaque dataset, MIND networks were more reliable, more consistent with cortical cytoarchitectonics and symmetry and more correlated with tract-tracing measures of axonal connectivity. MIND networks derived from human T1-weighted MRI were more sensitive to age-related changes than MSNs or networks derived by tractography of diffusion-weighted MRI. Gene co-expression between cortical areas was more strongly coupled to MIND networks than to MSNs or tractography. MIND network phenotypes were also more heritable, especially edges between structurally differentiated areas. MIND network analysis provides a biologically validated lens for cortical connectomics using readily available MRI data.
Resilient functioning is associated with altered structural brain network topology in adolescents exposed to childhood adversity
(Cambridge University Press, 2023-07-26) González-García, Nadia; Buimer, Elizabeth E.L.; Moreno-López, Laura; Sallie, Samantha N.; Váša, František; Lim, Sol; Romero García, Rafael; Van Harmelen, Anne Laura; NSPN Consortium; Fisiología Médica y Biofísica; Neuroscience in Psychiatry Network (NSPN) Consortium; Royal Society UK; Wellcome Trust
Childhoodadversityis oneofthestrongestpredictors ofadolescentmentalillness.Therefore, it is critical that the mechanisms thataid resilient functioning in individuals exposed to childhood adversity are better understood. Here, we examined whether resilient functioning was related to structural brain network topology. We quantified resilient functioning at the individual level as psychosocial functioning adjusted for the severity of childhood adversity in a large sample of adolescents (N = 2406, aged 14–24). Next, we examined nodal degree (the number of connections that brain regions have in a network) using brain-wide cortical thickness measures in a representative subset (N = 275) using a sliding window approach. Wefoundthathigherresilient functioning was associated with lower nodal degree of multiple regions including the dorsolateral prefrontal cortex, the medial prefrontal cortex, and the posterior superior temporal sulcus (z > 1.645). During adolescence, decreases in nodal degree are thought to reflect a normative developmental process that is part of the extensive remodeling of structural brain network topology. Prior findings in this sample showed that decreased nodal degree was associated with age, as such our findings of negative associations between nodal degree and resilient functioning may therefore potentially resemble a more mature structural network configuration in individuals with higher resilient functioning
Orai1α and Orai1β support calcium entry and mammosphere formation in breast cancer stem cells
(Nature Publishing Group, 2023-11-09) Jardin, Isaac; Alvarado, Sandra; Jimenez-Velarde, Vanesa; Nieto-Felipe, Joel; Lopez, Jose J.; Salido, Gines M.; Smani Hajami, Tarik; Rosado, Juan A.; Fisiología Médica y Biofísica; Ministerio de Ciencia e Innovación (MICIN). España; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
Orai1 is the pore-forming subunit of the Ca2+-release activated Ca2+ channels that mediate store-operated Ca2+ entry (SOCE) in excitable and non-excitable cells. Two Orai1 forms have been identified in mammalian cells, the full-length variant Orai1α, and the short form Orai1β, lacking the N-terminal 63 amino acids. Stem cells were isolated from non-tumoral breast epithelial cells of the MCF10A cell line, and the most representative ER+ , HER2 or triple negative breast cancer cell lines MCF7, SKBR3 and MDA-MB-231, respectively. Orai and TRPC family members expression was detected by RT-PCR and Western blotting. Changes in cytosolic Ca2+ concentration were analyzed by confocal microscopy using Fluo 4 and the spheroid-forming ability and self-renewal was estimated in culture plates coated with pHEMA using a cell imaging system. Here, we have characterized the expression of Orai family members and several TRPC channels at the transcript level in breast stem cells (BSC) derived from the non-tumoral breast epithelial cell line MCF10A and breast cancer stem cells (BCSC) derived from the well-known estrogen receptor positive (ER+), HER2 and triple negative cell lines MCF7, SKBR3 and MDA-MB-231, respectively. Furthermore, we have evaluated the mammosphere formation efficiency and self-renewal of the BSC and BCSC. Next, through a combination of Orai1 knockdown by iRNA and the use of MDA-MB-231 KO cells, missing the native Orai1, transfected with plasmids encoding for either Orai1α or Orai1β, we show that Orai1 is essential for mammosphere formation and self-renewal efficiency in BCSC derived from triple negative and HER2 subtypes cell cultures, while this channel has a negligible effect in BCSC derived from ER+ cells as well as in non-tumoral BSC. Both, Orai1α, and Orai1β support SOCE in MDA-MB-231-derived BCSC with similar efficiency, as well as COX activation and mammosphere formation. These findings provide evidence of the functional role of Orai1α and Orai1β in spheroid forming efficiency and self-renewal in breast cancer stem cells.
Nifedipine Ameliorates Cellular Differentiation Defects of Smn-Deficient Motor Neurons and Enhances Neuromuscular Transmission in SMA Mice
(MDPI, 2023-04-21) Tejero, Rocío; Alsakkal, Mohammad; Hennlein, Luisa; López-Cabello, Ana M.; Jablonka, Sibylle; Tabares, Lucía; Fisiología Médica y Biofísica; Marató de TV3 Foundation; Agencia Estatal de Investigación. España; Deutsche Forschungsgemeinschaft / German Research Foundation (DFG); Cure SMA
In spinal muscular atrophy (SMA), mutations in or loss of the Survival Motor Neuron 1 (SMN1) gene reduce full-length SMN protein levels, which leads to the degeneration of a percentage of motor neurons. In mouse models of SMA, the development and maintenance of spinal motor neurons and the neuromuscular junction (NMJ) function are altered. Since nifedipine is known to be neuroprotective and increases neurotransmission in nerve terminals, we investigated its effects on cultured spinal cord motor neurons and motor nerve terminals of control and SMA mice. We found that application of nifedipine increased the frequency of spontaneous Ca2+ transients, growth cone size, cluster-like formations of Cav2.2 channels, and it normalized axon extension in SMA neurons in culture. At the NMJ, nifedipine significantly increased evoked and spontaneous release at low-frequency stimulation in both genotypes. High-strength stimulation revealed that nifedipine increased the size of the readily releasable pool (RRP) of vesicles in control but not SMA mice. These findings provide experimental evidence about the ability of nifedipine to prevent the appearance of developmental defects in SMA embryonic motor neurons in culture and reveal to which extent nifedipine could still increase neurotransmission at the NMJ in SMA mice under different functional demands
New Insights into the Reparative Angiogenesis after Myocardial Infarction
(MDPI, 2023-08-01) Martín-Bórnez, Marta; Falcón Boyano, Débora; Morrugares, Rosario; Siegfried, Geraldine; Khatib, Abdel Majid; Rosado, Juan A.; Galeano-Otero, Isabel; Smani Hajami, Tarik; Fisiología Médica y Biofísica; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; Junta de Andalucía; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Ministerio de Ciencia, Innovación y Universidades (MICIU). España
Myocardial infarction (MI) causes massive loss of cardiac myocytes and injury to the coronary microcirculation, overwhelming the limited capacity of cardiac regeneration. Cardiac repair after MI is finely organized by complex series of procedures involving a robust angiogenic response that begins in the peri-infarcted border area of the infarcted heart, concluding with fibroblast proliferation and scar formation. Efficient neovascularization after MI limits hypertrophied myocytes and scar extent by the reduction in collagen deposition and sustains the improvement in cardiac function. Compelling evidence from animal models and classical in vitro angiogenic approaches demonstrate that a plethora of well-orchestrated signaling pathways involving Notch, Wnt, PI3K, and the modulation of intracellular Ca2+ concentration through ion channels, regulate angiogenesis from existing endothelial cells (ECs) and endothelial progenitor cells (EPCs) in the infarcted heart. Moreover, cardiac repair after MI involves cell-to-cell communication by paracrine/autocrine signals, mainly through the delivery of extracellular vesicles hosting pro-angiogenic proteins and non-coding RNAs, as microRNAs (miRNAs). This review highlights some general insights into signaling pathways activated under MI, focusing on the role of Ca2+ influx, Notch activated pathway, and miRNAs in EC activation and angiogenesis after MI.
Mitochondrial integrated stress response controls lung epithelial cell fate
(Nature Pub. Group, 2023-08-09) Han, SeungHye; Lee, Minho; Shin, Youngjin; Giovanni, Regina; Chakrabarty, Ram P.; Herrerias, Mariana M.; Dada, Laura A; Flozak, Annette S.; Reyfman, Paul A.; Khuder, Basil; Reczek, Colleen R.; Gao Chen, Lin; López Barneo, José; Chandel, Navdeep S.; Fisiología Médica y Biofísica; American Heart Association Career Development Award; National Institutes for Health (NIH); National Research Foundation of Korea; NCI
Alveolar epithelial type 1 (AT1) cells are necessary to transfer oxygen and carbon dioxide between the blood and air. Alveolar epithelial type 2 (AT2) cells serve as a partially committed stem cell population, producing AT1 cells during postnatal alveolar development and repair after influenza A and SARS-CoV-2 pneumonia1,2,3,4,5,6. Little is known about the metabolic regulation of the fate of lung epithelial cells. Here we report that deleting the mitochondrial electron transport chain complex I subunit Ndufs2 in lung epithelial cells during mouse gestation led to death during postnatal alveolar development. Affected mice displayed hypertrophic cells with AT2 and AT1 cell features, known as transitional cells. Mammalian mitochondrial complex I, comprising 45 subunits, regenerates NAD+ and pumps protons. Conditional expression of yeast NADH dehydrogenase (NDI1) protein that regenerates NAD+ without proton pumping7,8 was sufficient to correct abnormal alveolar development and avert lethality. Single-cell RNA sequencing revealed enrichment of integrated stress response (ISR) genes in transitional cells. Administering an ISR inhibitor9,10 or NAD+ precursor reduced ISR gene signatures in epithelial cells and partially rescued lethality in the absence of mitochondrial complex I function. Notably, lung epithelial-specific loss of mitochondrial electron transport chain complex II subunit Sdhd, which maintains NAD+ regeneration, did not trigger high ISR activation or lethality. These findings highlight an unanticipated requirement for mitochondrial complex I-dependent NAD+ regeneration in directing cell fate during postnatal alveolar development by preventing pathological ISR induction.
Thioredoxin and glutaredoxin regulate metabolism through different multiplex thiol switches
(Elsevier, 2019) López-Grueso, MJ; González-Ojeda, R; Requejo-Aguilar, R; McDonagh, B.; Fuentes-Almagro, C. A.; Muntané Relat, Jordi; Padilla, CA; Fisiología Médica y Biofísica; Ministerio de Economía y Competitividad (MINECO). España; Junta de Andalucía; Instituto de Salud Carlos III; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
The aim of the present study was to define the role of Trx and Grx on metabolic thiol redox regulation and identify their protein and metabolite targets. The hepatocarcinoma-derived HepG2 cell line under both normal and oxidative/nitrosative conditions by overexpression of NO synthase (NOS3) was used as experimental model. Grx1 or Trx1 silencing caused conspicuous changes in the redox proteome reflected by significant changes in the reduced/oxidized ratios of specific Cys's including several glycolytic enzymes. Cys91 of peroxiredoxin-6 (PRDX6) and Cys153 of phosphoglycerate mutase-1 (PGAM1), that are known to be involved in progression of tumor growth, are reported here for the first time as specific targets of Grx1. A group of proteins increased their CysRED/CysOX ratio upon Trx1 and/or Grx1 silencing, including caspase-3 Cys163, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) Cys247 and triose-phosphate isomerase (TPI) Cys255 likely by enhancement of NOS3 auto-oxidation. The activities of several glycolytic enzymes were also significantly affected. Glycolysis metabolic flux increased upon Trx1 silencing, whereas silencing of Grx1 had the opposite effect. Diversion of metabolic fluxes toward synthesis of fatty acids and phospholipids was observed in siRNA-Grx1 treated cells, while siRNA-Trx1 treated cells showed elevated levels of various sphingomyelins and ceramides and signs of increased protein degradation. Glutathione synthesis was stimulated by both treatments. These data indicate that Trx and Grx have both, common and specific protein Cys redox targets and that down regulation of either redoxin has markedly different metabolic outcomes. They reflect the delicate sensitivity of redox equilibrium to changes in any of the elements involved and the difficulty of forecasting metabolic responses to redox environmental changes.
Formaldehyde-assisted Isolation of Regulatory Elements to Measure Chromatin Accessibility in Mammalian Cells
(MYJoVE Corp, 2018-02-04) Rodríguez Gil, Alfonso; Riedlinger, Tabea; Ritter, Olesja; Vera, V. Saúl; Schmitz, M. Lienhard; Fisiología Médica y Biofísica; Deutsche Forschungsgemeinschaft; Deutsche Krebshilfe
Appropriate gene expression in response to extracellular cues, that is, tissue- and lineage-specific gene transcription, critically depends on highly defined states of chromatin organization. The dynamic architecture of the nucleus is controlled by multiple mechanisms and shapes the transcriptional output programs. It is, therefore, important to determine locus-specific chromatin accessibility in a reliable fashion that is preferably independent from antibodies, which can be a potentially confounding source of experimental variability. Chromatin accessibility can be measured by various methods, including the Formaldehyde-Assisted Isolation of Regulatory Elements (FAIRE) assay, that allow the determination of general chromatin accessibility in a relatively low number of cells. Here we describe a FAIRE protocol that allows simple, reliable, and fast identification of genomic regions with a low protein occupancy. In this method, the DNA is covalently bound to the chromatin proteins using formaldehyde as a crosslinking agent and sheared to small pieces. The free DNA is afterwards enriched using phenol:chloroform extraction. The ratio of free DNA is determined by quantitative polymerase chain reaction (qPCR) or DNA sequencing (DNA-seq) compared to a control sample representing total DNA. The regions with a looser chromatin structure are enriched in the free DNA sample, thus allowing the identification of genomic regions with lower chromatin compaction.
Serum Metabolites as Diagnostic Biomarkers for Cholangiocarcinoma, Hepatocellular Carcinoma, and Primary Sclerosing Cholangitis
(Willey, 2019-08) Banales, Jesus M.; Iñarrairaegui, Mercedes; Arbelaiz, Ander; Milkiewicz, Piotr; Muntané Relat, Jordi; Muñoz‐Bellvis, Luis; Macias, Rocio I.R.; Fisiología Médica y Biofísica; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Ministerio de Economía y Competitividad (MINECO). España; Instituto de Salud Carlos III; Diputación Foral de Gipuzkoa; Gobierno Vasco; Junta de Andalucía; Junta de Castilla-León; European Union (UE). H2020
Early and differential diagnosis of intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) by noninvasive methods represents a current clinical challenge. The analysis of low‐molecular‐weight metabolites by new high‐throughput techniques is a strategy for identifying biomarkers. Here, we have investigated whether serum metabolome can provide useful biomarkers in the diagnosis of iCCA and HCC and could discriminate iCCA from HCC. Because primary sclerosing cholangitis (PSC) is a risk factor for CCA, serum metabolic profiles of PSC and CCA have also been compared. The analysis of the levels of lipids and amino acids in the serum of patients with iCCA, HCC, and PSC and healthy individuals (n = 20/group) showed differential profiles. Several metabolites presented high diagnostic value for iCCA versus control, HCC versus control, and PSC versus control, with areas under the receiver operating characteristic curve (AUC) greater than those found in serum for the nonspecific tumor markers carbohydrate antigen 19‐9 (CA 19‐9) and alpha‐fetoprotein (AFP), commonly used to help in the diagnosis of iCCA and HCC, respectively. The development of an algorithm combining glycine, aspartic acid, SM(42:3), and SM(43:2) permitted to accurately differentiate in the diagnosis of both types of tumors (biopsy‐proven). The proposed model yielded 0.890 AUC, 75% sensitivity, and 90% specificity. Another algorithm by combination of PC(34:3) and histidine accurately permitted to differentiate PSC from iCCA, with an AUC of 0.990, 100% sensitivity, and 70% specificity. These results were validated in independent cohorts of 14‐15 patients per group and compared with profiles found in patients with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Conclusion: Specific changes in serum concentrations of certain metabolites are useful to differentiate iCCA from HCC or PSC, and could help in the early diagnosis of these diseases.
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 Foundation
Survival 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.
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 Andalucía
Metabotropic 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.
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 Lagos
Pudu 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.
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 engineeRING
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; NIH
How 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.
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 Society
The 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.
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 Foundation
The 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.
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 Fund
Cortisol 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.

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