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Focal cortical dysplasia (FCD) is a brain malformation that causes medically refractory epilepsy. FCD is classified into three categories based on structural and cellular abnormalities, with FCD type II being the most common and characterized by disrupted organization of the cortex and abnormal neuronal development. In this study, we employed cell-type deconvolution and single-cell signatures to analyze bulk RNA-seq from multiple transcriptomic studies, aiming to characterize the cellular composition of brain lesions in patients with FCD IIa and IIb subtypes. Our deconvolution analyses revealed specific cellular changes in FCD IIb, including neuronal loss and an increase in reactive astrocytes (astrogliosis) when compared to FCD IIa. Astrogliosis in FCD IIb was further supported by a gene signature analysis and histologically confirmed by glial fibrillary acidic protein (GFAP) immunostaining. Overall, our findings demonstrate that FCD II subtypes exhibit differential neuronal and glial compositions, with astrogliosis emerging as a hallmark of FCD IIb. These observations, validated in independent patient cohorts and confirmed using immunohistochemistry, offer novel insights into the involvement of glial cells in FCD type II pathophysiology and may contribute to the development of targeted therapies for this condition.

Objective Mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) are brain lesions associated with focal epilepsy and characterized by increased oligodendroglial density, heterotopic neurons, and hypomyelination in the white matter. While previous studies have implicated somatic mutations in the SLC35A2 gene, the cellular and molecular mechanisms underlying MOGHE pathogenesis remain elusive. To address this gap, this study aimed to systematically characterize the cell type composition and molecular alterations of MOGHE lesions at cellular resolution using single-nucleus multiomics profiling. Methods We performed single-nucleus multiomics sequencing to obtain paired gene expression and chromatin accessibility profiles of > 31,000 nuclei from gray matter and white matter regions of MOGHE lesions, and compared the results with publicly available neurotypical control datasets. Results The analysis of gray and white matter regions from two MOGHE patients revealed significant cellular composition alterations, including the presence of heterotopic neurons and disease-specific oligodendrocytes populations within the subcortical white matter. MOGHE-specific oligodendrocytes were characterized by the upregulation of synaptic functions and enhanced neuron communication, denoting a possible role in synaptic support and the mediation of glial-neuron interactions in the disease. On the other hand, MOGHE heterotopic neurons were characterized by the upregulation of genes associated with neuronal migration and the Wnt signaling pathway, suggesting a mechanism underlying their atypical localization. Significance This high-resolution cell type mapping of MOGHE lesions in clinical samples unveils neuronal and glial populations affected by the disease, and provides novel insights into the pathophysiological mechanisms of MOGHE.

Focal Cortical Dysplasia (FCD) is a neurodevelopmental condition characterized by malformations of the cerebral cortex that often cause drug-resistant epilepsy. In this study, we performed multi-omics single-cell profiling to map the chromatin accessibility and transcriptome landscapes of FCD type II, generating a comprehensive multimodal single-cell dataset comprising 61,525 cells from 11 clinical samples of lesions and controls. Our findings revealed profound chromatin, transcriptomic, and cellular alterations affecting neuronal and glial cells in FCD lesions, including the selective loss of upper-layer excitatory neurons, significant expansion of oligodendrocytes and immature astrocytic populations, and a unique neuronal subpopulation harboring dysmorphic neurons. Furthermore, we uncovered activated microglia subsets, particularly in FCD IIb cases. This comprehensive study unveils neuronal and glial cell states driving FCD development and epileptogenicity, enhancing our understanding of FCD and offering new directions for targeted therapy development.

Focal cortical dysplasia (FCD) is a brain malformation that causes medically refractory epilepsy. FCD is classified into three categories based on structural and cellular abnormalities, with FCD type II being the most common and characterized by disrupted organization of the cortex and abnormal neuronal development. In this study, we employed cell-type deconvolution and single-cell signatures to analyze bulk RNA-seq from multiple transcriptomic studies, aiming to characterize the cellular composition of brain lesions in patients with FCD IIa and IIb subtypes. Our deconvolution analyses revealed specific cellular changes in FCD IIb, including neuronal loss and an increase in reactive astrocytes (astrogliosis) when compared to FCD IIa. Astrogliosis in FCD IIb was further supported by a gene signature analysis and histologically confirmed by glia fibrilla acidic protein (GAP) immunostaining. Overall, our findings demonstrate that FCD II subtypes exhibit differential neuronal and glial compositions, with astrogliosis emerging as a hallmark of FCD IIb. These observations, validated in independent patient cohorts and confirmed using immunohistochemistry, offer novel insights into the involvement of glial cells in FCD type II pathophysiology and may contribute to the development of targeted therapies for this condition.

Lipid nanoparticles, both solid lipid nanoparticles and nanostructured lipid carriers (NLC), containing tacrolimus (FK) were obtained by solvent diffusion method associated with ultrasonication using stearic acid (SA) or beeswax as solid lipid. The oleic acid was used as liquid lipid in the NLC. Lipid nanoparticles were characterized by determining the drug loading, particle size, polydispersity index (PDI) and zeta potential (ZP). Analysis by differential scanning calorimetry and X-ray diffraction were performed. Lipid nanoparticles presented nano-sized from 139 to 275 nm. The PDI results show the particles present from 0.3 to 0.5, and ZP was higher than |25| mV. Drug loading ranged of 2.3–3.2%. SA nanoparticles presented better ZP, average size and distribution. However, beeswax nanoparticles showed higher drug loading. Results suggest there are no incompatibilities between FK and the raw materials. Polymorphic modifications were not observed. The results presented show that lipid nanoparticles using both lipids were successfully obtained and may represent promising delivery system of FK in topical formulations.

Nonphlogistic migration of macrophages contributes to the clearance of pathogens and apoptotic cells, a critical step for the resolution of inflammation and return to homeostasis. Angiotensin-(1-7) [Ang-(1-7)] is a heptapeptide of the renin-angiotensin system that acts through Mas receptor (MasR). Ang-(1-7) has recently emerged as a novel proresolving mediator, yet Ang-(1-7) resolution mechanisms are not fully determined. Herein, Ang-(1-7) stimulated migration of human and murine monocytes/macrophages in a MasR-, CCR2-, and MEK/ERK1/2–dependent manner. Pleural injection of Ang-(1-7) promoted nonphlogistic mononuclear cell influx alongside increased levels of CCL2, IL-10, and macrophage polarization toward a regulatory phenotype. Ang-(1-7) induction of CCL2 and mononuclear cell migration was also dependent on MasR and MEK/ERK. Of note, MasR was upregulated during the resolution phase of inflammation, and its pharmacological inhibition or genetic deficiency impaired mononuclear cell recruitment during self-resolving models of LPS pleurisy and E . coli peritonitis. Inhibition/absence of MasR was associated with reduced CCL2 levels, impaired phagocytosis of bacteria, efferocytosis, and delayed resolution of inflammation. In summary, we have uncovered a potentially novel proresolving feature of Ang-(1-7), namely the recruitment of mononuclear cells favoring efferocytosis, phagocytosis, and resolution of inflammation. Mechanistically, cell migration was dependent on MasR, CCR2, and the MEK/ERK pathway.

Introduction For the most part, migraine afflicts young women who often need to use the hormonal contraceptive method. Objective To evaluate the effects of using exogenous estrogen, present in combined hormonal contraceptives (CHC) and progestin-only methods on the prevalence of allodynia in women with migraine. Methods Study comprising women diagnosed with migraine, with or without aura, who were not pregnant, breastfeeding, or menopausal. The study was conducted via the digital platform. Data were collected relating to demographics, contraceptive method, anthropometric information, smoking habits, and migraine-related symptoms. The participants then answered the following validated, self-administered questionnaires: Migraine Disability Assessment (MIDAS), Allodynia Symptom Checklist, Generalized Anxiety Disorder (GAD-7), and Beck’s Depression Inventory (BDI). In order to determine the variables associated with allodynia, two binary logistic regression models were used. Results Four hundred eighty-six women took part in the study. Of these, 205 used CHC, 89 used a progestin-only method, and 192 participants did not use any form of hormonal contraception. Allodynia was identified in 411 (84.6%) participants. Allodynia was linked to the presence of aura (OR = 2.76; CI 95% 1.55–4.91; p  = 0.001), menstrually related migraine (OR = 2.14; CI 95% 1.28–3.57; p  = 0.004), greater disability (MIDAS score 23 vs. 8; p  < 0.001), depression (BDI score 14 vs. 10; p  < 0.001), and anxiety (GAD-7 score 11 vs. 8; p  < 0.001). In adjusted analysis, CHC was associated to protection against allodynia when jointly evaluated all CHC regimens (OR = 0.49 CI 95% 0.26–0.92; p  = 0.028), as well as oral CHC individually (OR = 0.48 CI 95% 0.25–0.92; p  = 0.027). Conclusion CHC reduced the chances of women with migraine getting allodynia.

This short note aims to report in detail a preliminary assessment of the concentrations of Cd, Hg and Pb in tissues of blue crabs Callinectes danae collected from the Cananéia-Iguape-Peruíbe estuarine complex (CIP), in the South of São Paulo State coast, Brazil. In October 2014, blue crabs were collected from CIP. Tissues were removed by dissection and metal determination was performed by GF-AAS and CV-AAS. According to statistical analysis, Pb and Cd concentrations in gills were significantly higher than those found in muscles and hepatopancreas, respectively. There were no significant differences in Hg concentrations between samples. Cd, Hg and Pb concentrations in gills and hepatopancreas were lower than those reported in a previous study performed at CIP. However, Cd concentration in hepatopancreas was higher than the Brazilian limit for consumption and new efforts to monitor Cd concentrations in C. danae tissues must be performed.

This technical note aims to report, in detail, the development, suitability and analytical validation of an artificial food to assess metal bioaccumulation in the blue crab Callinectes danae after metal exposure assays. For this purpose, lead (Pb) was chosen as the metal of interest. First, a non-contaminated artificial food was prepared by mixing commercial shrimps and agarose. The food was then offered on alternate days to two groups of crabs for 7 and 14 days, respectively. After confirming that this food was well-accepted by crabs, analytical procedures were performed to confirm that Pb added to the mixture would remain in the artificial food. For this purpose, two foods containing Pb at concentrations of 0.5 and 2.0 µg g−1 were prepared by adding aliquots of an ultrapure Pb standard solution to the mixture. Samples of each food were subjected to an acid extraction and Pb concentrations were determined by a GF-AAS. Pb recoveries in both contaminated foods were > 90%. Subsequently, another experiment was performed, and two groups of crabs were fed with contaminated artificial foods (0.5 and 2.0 µg g−1 of Pb) during 7 and 14 days, respectively. The observed acceptance of these foods by crabs at both Pb concentrations was of 100%.An artificial food was prepared to assess bioaccumulation in the blue crabLead (Pb) was chosen as the metal of interestThe acceptance of artificial food was evaluatedIn the contaminated artificial foods, Pb was determinedIt was concluded that this food can be applied in metal exposure assays

Exacerbated inflammation is a major contributor to tissue damage and mortality in infectious diseases, including SARS-CoV-2. The resolution phase of inflammation is critical for restoring tissue homeostasis following an injury. Annexin A1 (AnxA1) is a ubiquitous protein that plays a fundamental role in the resolution of inflammation, including in preclinical models of infectious disease. Here, we investigated the role of AnxA1 in coronavirus infection and its potential as a host-targeted therapeutic strategy against SARS-CoV-2. Wild-type (WT) and AnxA1 knockout (AnxA1KO) mice were intranasally infected with the murine betacoronavirus MHV-3 to study the endogenous role of AnxA1. Immunohistochemistry and Western blot analyses in the lungs of MHV-3-infected mice revealed increased AnxA1 expression and its cleavage, which was associated with neutrophilic infiltration (Ly6G+ cells) mainly in peribronchiolar and perivascular regions. AnxA1-deficient mice exhibited higher neutrophilic infiltration and lung damage, alongside increased CXCL1 production in the lungs, when compared to WT-infected mice. In a murine model of SARS-CoV-2 infection in K18-hACE2 mice, we found increased AnxA1 cleavage associated with lung inflammation. Treatment of SARS-CoV-2-infected K18-hACE2 mice with the AnxA1-mimetic peptide, Ac2-26, reduced lung damage and lethality, without altering the host ability to deal with viral replication. Notably, Ac2-26-treated mice exhibited similar levels of protection to that afforded by the nucleotide analogue Remdesivir, following SARS-CoV-2 infection. Our findings highlight the protective role of the endogenous AnxA1 in mitigating coronavirus-induced lung inflammation and underscore the therapeutic potential of AnxA1 mimetic Ac2-26 as a host-targeted therapy against SARS-CoV-2.Competing Interest StatementThe authors have declared no competing interest.