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Cell Reports Jun 2023Synaptic plasticity is hypothesized to underlie "replay" of salient experience during hippocampal sharp-wave/ripple (SWR)-based ensemble activity and to facilitate...
Synaptic plasticity is hypothesized to underlie "replay" of salient experience during hippocampal sharp-wave/ripple (SWR)-based ensemble activity and to facilitate systems-level memory consolidation coordinated by SWRs and cortical sleep spindles. It remains unclear how molecular changes at synapses contribute to experience-induced modification of network function. The synaptic protein KIBRA regulates plasticity and memory. To determine the impact of KIBRA-regulated plasticity on circuit dynamics, we recorded in vivo neural activity from wild-type (WT) mice and littermates lacking KIBRA and examined circuit function before, during, and after novel experience. In WT mice, experience altered population activity and oscillatory dynamics in a manner consistent with incorporation of new information content in replay and enhanced hippocampal-cortical communication. While baseline SWR features were normal in KIBRA conditional knockout (cKO) mice, experience-dependent alterations in SWRs were absent. Furthermore, intra-hippocampal and hippocampal-cortical communication during SWRs was disrupted following KIBRA deletion. These results indicate molecular mechanisms that underlie network-level adaptations to experience.
Topics: Animals; Mice; Hippocampus; Memory Consolidation; Sleep
PubMed: 37347662
DOI: 10.1016/j.celrep.2023.112662 -
Frontiers in Molecular Neuroscience 2021Extracellular vesicles (EVs) have emerged in the last decade as critical cell-to-cell communication devices used to carry nucleic acids and proteins between cells. EV... (Review)
Review
Extracellular vesicles (EVs) have emerged in the last decade as critical cell-to-cell communication devices used to carry nucleic acids and proteins between cells. EV cargo includes plasma membrane and endosomal proteins, but EVs also contain material from other cellular compartments, including mitochondria. Within cells, mitochondria are responsible for a large range of metabolic reactions, but they can also produce damaging levels of reactive oxygen species and induce inflammation when damaged. Consistent with this, recent evidence suggests that EV-mediated transfer of mitochondrial content alters metabolic and inflammatory responses of recipient cells. As EV mitochondrial content is also altered in some pathologies, this could have important implications for their diagnosis and treatment. In this review, we will discuss the nature and roles of mitochondrial EVs, with a special emphasis on the nervous system.
PubMed: 34751216
DOI: 10.3389/fnmol.2021.767219 -
Antioxidants (Basel, Switzerland) Apr 2023Pulmonary hypertension (PH) is a progressive disease characterized by elevated artery pressures and pulmonary vascular resistance. Underlying mechanisms comprise... (Review)
Review
Pulmonary hypertension (PH) is a progressive disease characterized by elevated artery pressures and pulmonary vascular resistance. Underlying mechanisms comprise endothelial dysfunction, pulmonary artery remodeling and vasoconstriction. Several studies have shown evidence of the critical role of oxidative stress in PH pathophysiology. Alteration of redox homeostasis produces excessive generation of reactive oxygen species, inducing oxidative stress and the subsequent alteration of biological molecules. Exacerbations in oxidative stress production can lead to alterations in nitric oxide signaling pathways, contributing to the proliferation of pulmonary arterial endothelial cells and smooth muscle cells, inducing PH development. Recently, antioxidant therapy has been suggested as a novel therapeutic strategy for PH pathology. However, the favorable outcomes observed in preclinical studies have not been consistently reproduced in clinical practice. Therefore, targeting oxidative stress as a therapeutic intervention for PH is an area that is still being explored. This review summarizes the contribution of oxidative stress to the pathogenesis of the different types of PH and suggests antioxidant therapy as a promising strategy for PH treatment.
PubMed: 37237872
DOI: 10.3390/antiox12051006 -
Journal of the Endocrine Society Oct 2022Gestational diabetes mellitus (GDM) results in an increased risk of pre- and postpartum health complications for both mother and child. Metabolomics analysis can... (Review)
Review
Gestational diabetes mellitus (GDM) results in an increased risk of pre- and postpartum health complications for both mother and child. Metabolomics analysis can potentially identify predictive biomarkers and provide insight into metabolic alterations associated with GDM pathogenesis and progression, but few metabolomics studies investigate alterations observed across the first and third trimester. We hypothesize that metabolites altered in first-trimester GDM that remain altered in late pregnancy may best inform interventions. Metabolomic studies comparing plasma and serum metabolite alterations in GDM vs non-GDM pregnancies were retrieved by searching PubMed, Medline, and CINAHL Plus databases. The present scoping review summarizes the metabolites found to be consistently altered throughout the course of GDM and proposes mechanisms that explain how these metabolic perturbations relate to GDM development and progression. Metabolites involved in fatty acid metabolism, reductive carboxylation, branched-chain amino acid metabolism, cell membrane lipid metabolism, purine degradation, and the gut microbiome were found to be altered throughout GDM pregnancies, with many of these pathways showing mechanistic links to insulin resistance, inflammation, and impaired cell signaling. Future studies are required to investigate if normalization of these perturbed pathways can be the targets of interventions.
PubMed: 36320628
DOI: 10.1210/jendso/bvac134 -
Frontiers in Systems Neuroscience 2019The present article reviews the relationship between sleep and oscillatory activity in Down Syndrome (DS), as well as the featuring emergent rhythmic activity across... (Review)
Review
The present article reviews the relationship between sleep and oscillatory activity in Down Syndrome (DS), as well as the featuring emergent rhythmic activity across different brain states. A comprehensive discussion of the data from electroencephalographic studies in DS humans and transgenic/trisomic mouse models is provided, as well as data from signals collected from local field potentials (LFP) and intracellular recordings in DS mouse models. The first sections focus specially on the alpha phenotype consistently observed in DS subjects, as well as its description in DS childhood and aging. Subsequently, a review of the data reported in DS mouse models is presented with the aim to deepen on the mechanisms underlying altered rhythmic patterns. Further sections situate the state-of-the-art of the field, with a discussion on the possible circuit alterations that may underlie impaired alpha and gamma oscillatory activity. A further aim is to highlight the importance of studying network oscillatory activity in mouse models to infer alterations in the underlying circuits related to cognition, such as in intellectual disability. In this direction, a view of alpha and gamma rhythms generated by the cerebral cortex as a tool for evaluating an unbalance between excitation and inhibition in DS is claimed, which points out toward an over-inhibited network. A final aim is to situate oscillatory activity as a key phenomenon that may be used as a biomarker for monitoring as well the effect of novel therapeutic strategies.
PubMed: 31139056
DOI: 10.3389/fnsys.2019.00017 -
Journal of Atherosclerosis and... Aug 2018Ischemic cardiovascular disease is a major cause of morbidity and mortality worldwide and thrombus formation on disrupted atherosclerotic plaques is considered to... (Review)
Review
Ischemic cardiovascular disease is a major cause of morbidity and mortality worldwide and thrombus formation on disrupted atherosclerotic plaques is considered to trigger its onset. Although the activation of platelets and coagulation pathways has been investigated intensively, the mechanisms of thrombus formation on disrupted plaques have not been understood in detail. Platelets are thought to play a central role in the formation of arterial thrombus because of rapid flow conditions; however, thrombus that develops on disrupted plaques consistently includes large amounts of fibrin in addition to aggregated platelets. While, thrombus does not always become large enough to completely occlude the vascular lumen, indicating that the propagation of thrombus is also critical for the onset of cardiovascular events. Various factors, such as vascular wall thrombogenicity, altered blood flow and imbalanced blood hemostasis, modulate thrombus formation and propagation on disrupted plaques. Pathological findings derived from humans and experimental animal models of atherothrombosis have identified important factors that affect thrombus formation and propagation, namely platelets, extrinsic and intrinsic coagulation factors, proinflammatory factors, plaque hypoxia and blood flow alteration. These findings might provide insight into the mechanisms of thrombus formation and propagation on disrupted plaques that lead to the onset of cardiovascular events.
Topics: Animals; Cardiovascular Diseases; Humans; Thrombosis
PubMed: 29887539
DOI: 10.5551/jat.RV17022 -
BioRxiv : the Preprint Server For... May 2023Our data previously revealed that chemosurviving cancer cells translate specific genes. Here, we find that the m6A-RNA-methyltransferase, METTL3, increases transiently...
Our data previously revealed that chemosurviving cancer cells translate specific genes. Here, we find that the m6A-RNA-methyltransferase, METTL3, increases transiently in chemotherapy-treated breast cancer and leukemic cells in vitro and in vivo. Consistently, m6A increases on RNA from chemo-treated cells, and is needed for chemosurvival. This is regulated by eIF2α phosphorylation and mTOR inhibition upon therapy treatment. METTL3 mRNA purification reveals that eIF3 promotes METTL3 translation that is reduced by mutating a 5'UTR m6A-motif or depleting METTL3. METTL3 increase is transient after therapy treatment, as metabolic enzymes that control methylation and thus m6A levels on METTL3 RNA, are altered over time after therapy. Increased METTL3 reduces proliferation and anti-viral immune response genes, and enhances invasion genes, which promote tumor survival. Consistently, overriding phospho-eIF2α prevents METTL3 elevation, and reduces chemosurvival and immune-cell migration. These data reveal that therapy-induced stress signals transiently upregulate METTL3 translation, to alter gene expression for tumor survival.
PubMed: 37292633
DOI: 10.1101/2023.05.19.540602 -
Neuroscience and Biobehavioral Reviews Nov 2022Clinical empathy refers to the ability of healthcare providers (HP) to recognize and understand what patients feel. While neuroimaging investigations have identified a... (Meta-Analysis)
Meta-Analysis Review
Clinical empathy refers to the ability of healthcare providers (HP) to recognize and understand what patients feel. While neuroimaging investigations have identified a neural network of empathy, activation consistency of brain regions and their specific functions in clinical empathy remains unclear. Herein, we conducted meta-analyses of dispositional assessments using random-effects models and functional neuroimaging using Seed-based d Mapping with Permutation of Subject Images to ascertain the shared neural processes consistently identified as relevant to clinical empathy. The dispositional meta-analysis (n = 15) revealed that HP exhibited higher scores on empathic concern and perspective taking. The HP neuroimaging meta-analysis (n = 11) identified consistent activation of the anterior mid-cingulate cortex, anterior insula, and ventrolateral prefrontal cortex (vlPFC) while HP vs. controls comparison (n = 9) did not yield robust alterations. The vlPFC mediated positive and negative functional connectivity of the insula. We revisited the framework of emotion regulation in clinical empathy. The empathetic agent flexibly shifts between affective regulatory strategies to meet contextual demands, with vlPFC figuring as the key region where this neural mechanism takes place.
Topics: Humans; Empathy; Magnetic Resonance Imaging; Functional Neuroimaging; Emotions; Brain; Neuroimaging; Brain Mapping
PubMed: 36116577
DOI: 10.1016/j.neubiorev.2022.104874 -
Epilepsia Open Mar 2021Drug-resistant epileptic patients make up approximately one-third of the global epilepsy population. The pathophysiology of drug resistance has not been fully... (Review)
Review
Drug-resistant epileptic patients make up approximately one-third of the global epilepsy population. The pathophysiology of drug resistance has not been fully elucidated; however, current evidence suggests intestinal dysbiosis, as a possible etiopathogenic factor. Ketogenic diet, whose effect is considered to be mediated by alteration of gut microbiota synthesis, has long been administered in patients with medically refractory seizures, with positive outcomes. In this review, we present data derived from clinical studies regarding alterations of gut microbiome profile in drug-resistant epileptic patients. We further attempt to describe the mechanisms through which the gut microbiome modification methods (including ketogenic diet, pre- or probiotic administration) improve drug-resistant epilepsy, by reporting findings from preclinical and clinical studies. A comprehensive search of the published literature on the PubMed, Embase, and Web of science databases was performed. Overall, the role of gut microbiome in drug-resistant epilepsy is an area which shows promise for the development of targeted therapeutic interventions. More research is required to confirm the results from preliminary studies, as well as safety and effectiveness of altering gut bacterial composition, through the above-mentioned methods.
Topics: Diet, Ketogenic; Drug Resistant Epilepsy; Dysbiosis; Gastrointestinal Microbiome; Humans; Probiotics
PubMed: 33681645
DOI: 10.1002/epi4.12461 -
MBio Feb 2021CsrA is a posttranscriptional global regulator in Although CsrA is critical for survival within the mammalian host, the regulatory targets of CsrA remain mostly...
CsrA is a posttranscriptional global regulator in Although CsrA is critical for survival within the mammalian host, the regulatory targets of CsrA remain mostly unknown. To identify pathways controlled by CsrA, RNA-seq transcriptome analysis was carried out by comparing the wild type and the mutant grown to early exponential, mid-exponential, and stationary phases of growth. This enabled us to identify the global effects of CsrA-mediated regulation throughout the growth cycle. We found that CsrA regulates 22% of the transcriptome, with significant regulation within the gene ontology (GO) processes that involve amino acid transport and metabolism, central carbon metabolism, lipid metabolism, iron uptake, and flagellum-dependent motility. Through CsrA-RNA coimmunoprecipitation experiments, we found that CsrA binds to multiple mRNAs that encode regulatory proteins. These include transcripts encoding the major sigma factors RpoS and RpoE, which may explain how CsrA regulation affects such a large proportion of the transcriptome. Other direct targets include , encoding a central regulator in flagellar gene expression, and , encoding the virulence gene transcription factor AphA. We found that CsrA binds to the mRNA both and , and CsrA significantly increases AphA protein synthesis. The increase in AphA was due to increased translation, not transcription, in the presence of CsrA, consistent with CsrA binding to the transcript and enhancing its translation. CsrA is required for the virulence of and this study illustrates the central role of CsrA in virulence gene regulation., a Gram-negative bacterium, is a natural inhabitant of the aqueous environment. However, once ingested, this bacterium can colonize the human host and cause the disease cholera. In order to successfully transition between its aqueous habitat and the human host, the bacterium must sense changes in its environment and rapidly alter gene expression. Global regulators, including CsrA, play an integral role in altering the expression of a large number of genes to promote adaptation and survival, which is required for intestinal colonization. We used transcriptomics and a directed CsrA-RNA coimmunoprecipitation to characterize the CsrA regulon and found that CsrA alters the expression of more than 800 transcripts in Processes regulated by CsrA include motility, the rugose phenotype, and virulence pathways. CsrA directly binds to the transcript and positively regulates the production of the virulence regulator AphA. Thus, CsrA regulates multiple processes that have been linked to pathogenesis.
Topics: Bacterial Proteins; Gene Expression Regulation, Bacterial; RNA-Binding Proteins; Regulon; Trans-Activators; Transcriptome; Vibrio cholerae; Virulence
PubMed: 33531387
DOI: 10.1128/mBio.03380-20