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Microglial cells are the neuroimmune competent cells of the central nervous system. In the adult, microglia are responsible for screening the neuronal parenchyma searching for alterations in homeostasis. Chronic neuroinflammation plays a role in neurodegenerative disease. Indeed, microglia-mediated neuroinflammation is involved in the onset and progression of several disorders in the brain and retina. Microglial cell reactivity occurs in an orchestrated manner and propagates across the neural parenchyma spreading the neuroinflammatory signal from cell to cell. Extracellular vesicles are important vehicles of intercellular communication and act as message carriers across boundaries. Extracellular vesicles can be subdivided in several categories according to their cellular origin (apoptotic bodies, microvesicles and exosomes), each presenting, different but sometimes overlapping functions in cell communication. Mounting evidence suggests a role for extracellular vesicles in regulating microglial cell action. Herein, we explore the role of microglial extracellular vesicles as vehicles for cell communication and the mechanisms that trigger their release. In this review we covered the role of microglial extracellular vesicles, focusing on apoptotic bodies, microvesicles and exosomes, in the context of neurodegeneration and the impact of these vesicles derived from other cells in microglial cell reactivity.

Dendritic cell (DC) transmigration across the lymphatic endothelium is critical for the initiation and sustenance of immune responses. Under noninflammatory conditions, DC transit across the lymphatic endothelial cell (LEC) has been shown to be integrin independent. In contrast, there is increasing evidence for the participation of integrins and their ligands in DC transit across lymphatic endothelium under inflammation. In this sense, we describe the formation of ICAM-1 (CD54)-enriched three-dimensional structures on LEC/DC contacts, as these DCs adhere to inflamed skin lymphatic vessels and transmigrate into them. In vitro imaging revealed that under inflammation ICAM-1 accumulated on microvilli projections surrounding 60% of adhered DCs. In contrast, these structures were scarcely formed in noninflammatory conditions. Furthermore, ICAM-1-enriched microvilli were important in promoting DC transendothelial migration and DC crawling over the LEC surface. Microvilli formation was dependent on the presence of β-integrins on the DC side and on integrin conformational affinity to ligand. Finally, we observed that LEC microvilli structures appeared in close vicinity of CCL21 depots and that their assembly was partially inhibited by CCL21-neutralizing antibodies. Therefore, under inflammatory conditions, integrin ligands form three-dimensional membrane projections around DCs. These structures offer docking sites for DC transit from the tissue toward the lymphatic vessel lumen.

From early in life, experiences like prenatal stress profoundly affect long-term health and behavior. Fetal exposure to increased levels of glucocorticoids (GC), via maternal stress or through antenatal corticosteroid therapy (commonly used in women at risk of preterm birth), can disrupt brain development and raise the susceptibility to psychiatric disorders. Previous studies on prenatal exposure to synthetic GCs, such as dexamethasone (DEX), revealed impairments in neurogenesis and dendritic spine development. However, the impact of prenatal stress, specifically antenatal DEX exposure, on the gliovascular interface remains unclear. This interface, involving the relationship between astrocytes and blood vessels, is essential for healthy brain development. Astrocytic endfeet coverage and organization are crucial features of the gliovascular interface, and in this study, we evaluated these aspects through aquaporin-4 (AQ4) expression and organization along the lectin labelled-vasculature. At Postnatal Day 14, no differences in AQ4 expression were observed between males and females. However, prenatal stress induced by DEX exposure (50 μg/kg was administered subcutaneously to pregnant mice through gestational days 16, 17 and 18) significantly impacted this structure in females but not in males. Specifically, in female offspring prenatally exposed to DEX, AQ4 expression was significantly upregulated in the hippocampus, and its rearrangement was observed in the prefrontal cortex. A comparison of vascular density between male and female brains showed no significant sex differences in any analyzed regions, though male cerebellar vessel segments were shorter. Interestingly, prenatal stress caused morphological alterations in female brains, including increased vessel tortuosity, while no such changes were seen in males. In the hippocampus, prenatal DEX exposure reduced vessel segment length in males but did not affect females. In the cerebellum, DEX exposure increased vessel segment length in females. This study highlights sex-specific differences in the impact of prenatal stress on the gliovascular structure across various brain regions, suggesting AQ4 as a potential molecular target relevant to depressive-like behaviors in female offspring. Future studies are needed to correlate the gliovascular structural alterations found with functional disturbances and sex-specific mental health issues.

Abstract It is essential that intelligence assessment be integrated with creativity, although no instruments in Brazil do so. This research investigated the item difficulty and validity and reliability of the Bateria de Avaliação Intelectual e Criativa Infantil (BAICI) to address this gap. The first sample consisted of 612 children (54% M) aged 7 to 12 years, and the second sample consisted of 377 students (56% M), some of whom (N = 164) were already identified as exhibiting high skills/giftedness. Item analysis indicated the need to adjust the BAICI items. The results of a MANCOVA indicated that the BAICI exhibits evidence of validity with external variables because the group of gifted children was significantly distinguished from the group of students attending regular schools on tests of vocabulary, speed, logical thinking, and creativity. The study concludes that the BAICI has psychometric qualities that can be used in the psychological assessment of children. Resumo É essencial que a avaliação da inteligência seja integrada com a criatividade embora não existam instrumentos no país para essa finalidade. Esta pesquisa investigou a dificuldade dos itens e as evidências de validade e precisão da Bateria de Avaliação Intelectual e Criativa Infantil (BAICI) para oferecer uma avaliação mais completa do potencial infantil. A primeira amostra foi composta por 612 crianças (54% M), idade sete a 12 anos e a segunda de 377 estudantes (56% M), uma parte (N = 164) já identificadas com altas habilidades/superdotação. A análise pela TRI indicou a necessidade de ajuste de itens da BAICI. Os resultados pela MANCOVA indicaram que a BAICI possui evidências de validade com variáveis externas, pois o grupo de crianças superdotadas se distinguiu significativamente de estudantes de escolas regulares nos testes de vocabulário, rapidez, pensamento lógico e criatividade. Conclui-se que a BAICI possui qualidades psicométricas para ser utilizada na avaliação psicológica infantil. Resumen Es fundamental que la evaluación de la inteligencia se integre con la creatividad, aunque en el país no existen instrumentos para este fin. Esta investigación analizó las evidencias de validez y precisión de la Batería de Evaluación Intelectual y Creativa Infantil (BAICI) para proporcionar una evaluación más completa del potencial de los niños. La primera muestra estuvo compuesta por 612 niños (54% M), de 7 a 12 años, a su vez, la segunda por 377 estudiantes (56% M), una parte (N = 164) ya identificada con altas habilidades/superdotación. El análisis de la TRI indicó la necesidad de ajustar los ítems de la BAICI. Los resultados de MANCOVA indicaron que BAICI tiene evidencias de validez con variables externas, ya que el grupo de niños superdotados se distinguió significativamente de niños de escuelas regulares en las pruebas de vocabulario, velocidad, pensamiento lógico y creatividad. Se concluye que la BAICI tiene cualidades psicométricas para ser utilizada en la evaluación psicológica infantil.

Abstract The present study sought to identify the relationship between creativity and intelligence in gifted students. The sample consisted of 966 participants, aged between 7 and 17 years, classified as regular students (n=867) and criterion group (n=99), subdivided according to the area of prominence: academic (n=66), creative/artistic (n=33). The Giftedness Assessment Battery was applied to assess reasoning (verbal, logical, numerical, and abstract) and creativity (verbal and figural). The results indicated that, in the control group, the relationship between the total score for intelligence and the two types of creativity were significant and positive, and scores were higher for verbal creativity. Only the correlation between the total scores for intelligence and verbal creativity was positive and significant in the criterion group. Differences in the relationship between constructs were also found according to the identification of giftedness (academic and creative). Resumo O presente estudo buscou identificar a relação entre criatividade e inteligência em alunos regulares e com altas habilidades/superdotação. A amostra foi composta por 966 participantes, com idades entre 7 e 17 anos, classificados em estudantes regulares (n = 867) e grupo critério (n = 99), subdivididos de acordo com a área de destaque: acadêmica (n = 66), criativa/artística (n = 33). A Bateria de Avaliação das Altas Habilidades/Superdotação foi aplicada envolvendo subtestes de avaliação do raciocínio (verbal, lógico, numérico e abstrato) e criatividade (verbal e figural). Os resultados indicaram que, no grupo controle, a relação entre o total em inteligência e os dois tipos de criatividade se mostraram significativas e positivas, sendo mais alta em relação à criatividade verbal. No grupo critério, somente a correlação entre o total de inteligência e criatividade verbal foi positiva e significativa. Diferenças na relação entre os construtos também foram encontradas de acordo com a área de identificação da superdotação (acadêmica e criativa). Resumen El presente estudio buscó identificar la relación entre creatividad e inteligencia en estudiantes regulares y estudiantes superdotados. La muestra estuvo compuesta por 966 participantes, con edades entre 7 y 17 años, clasificados en estudiantes regulares (n = 867) y grupo criterio (n = 119), y subclasificados de acuerdo con el área de destaque: académico (n = 66) y creativo/artístico (n = 33). Se aplicó la Batería de Evaluación de la Superdotación con subpruebas para evaluar el razonamiento (verbal, lógico, numérico y abstracto) y la creatividad (verbal y figurativa). Los resultados indicaron diferentes relaciones de acuerdo con el grupo considerado. La relación entre el total en inteligencia y los dos tipos de creatividad se mostraron significativas y positivas en el grupo control, siendo mayor con relación a la creatividad verbal. En el grupo criterio, solo fue positiva y significativa la relación entre las puntuaciones totales de inteligencia y la creatividad verbal. También se encontraron diferencias en la relación entre los constructos según el área de identificación de superdotación (académica y creativa).

The dynamics of the interaction between Cytotoxic T Lymphocytes (CTL) and tumor cells has been addressed in depth, in particular using numerical simulations. However, stochastic mathematical models that take into account the competitive interaction between CTL and tumors undergoing immunoediting, a process of tumor cell escape from immunesurveillance, are presently missing. Here, we introduce a stochastic dynamical particle interaction model based on experimentally measured parameters that allows to describe CTL function during immunoediting. The model describes the competitive interaction between CTL and melanoma cell nodules and allows temporal and two-dimensional spatial progression. The model is designed to provide probabilistic estimates of tumor eradication through numerical simulations in which tunable parameters influencing CTL efficacy against a tumor nodule undergoing immunoediting are tested. Our model shows that the rate of CTL/tumor nodule productive collisions during the initial time of interaction determines the success of CTL in tumor eradication. It allows efficient cytotoxic function before the tumor cells acquire a substantial resistance to CTL attack, due to mutations stochastically occurring during cell division. Interestingly, a bias in CTL motility inducing a progressive attraction towards a few scout CTL, which have detected the nodule enhances early productive collisions and tumor eradication. Taken together, our results are compatible with a biased competition theory of CTL function in which CTL efficacy against a tumor nodule undergoing immunoediting is strongly dependent on guidance of CTL trajectories by scout siblings. They highlight unprecedented aspects of immune cell behavior that might inspire new CTL-based therapeutic strategies against tumors.

The aim of this study was to demonstrate that a defined cosmetic composition is able to induce an increase in the production of sulfated glycosaminoglycans (sGAGs) and/or proteoglycans and finally to demonstrate that the composition, through its combined action of enzyme production and synthesis of macromolecules, modulates organization and skin surface aspect with a benefit in antiaging applications. Gene expression was studied by quantitative reverse transcription polymerase chain reaction using normal human dermal fibroblasts isolated from a 45-year-old donor skin dermis. De novo synthesis of sGAGs and proteoglycans was determined using Blyscan™ assay and/or immunohistochemical techniques. These studies were performed on normal human dermal fibroblasts (41- and 62-year-old donors) and on human skin explants. Dermis organization was studied either ex vivo on skin explants using bi-photon microscopy and transmission electron microscopy or directly in vivo on human volunteers by ultrasound technique. Skin surface modification was investigated in vivo using silicone replicas coupled with macrophotography, and the mechanical properties of the skin were studied using Cutometer. It was first shown that mRNA expression of several genes involved in the synthesis pathway of sGAG was stimulated. An increase in the de novo synthesis of sGAGs was shown at the cellular level despite the age of cells, and this phenomenon was clearly related to the previously observed stimulation of mRNA expression of genes. An increase in the expression of the corresponding core protein of decorin, perlecan, and versican and a stimulation of their respective sGAGs, such as chondroitin sulfate and heparan sulfate, were found on skin explants. The biosynthesis of macromolecules seems to be correlated at the microscopic level to a better organization and quality of the dermis, with collagen fibrils having homogenous diameters. The dermis seems to be compacted as observed on images obtained by two-photon microscopy and ultrasound imaging. At the macroscopic level, this dermis organization shows a smoothed profile similar to a younger skin, with improved mechanical properties such as firmess. The obtained results demonstrate that the defined cosmetic composition induces the synthesis of sGAGs and proteoglycans, which contributes to the overall dermal reorganization. This activity in the dermis in turn impacts the surface and mechanical properties of the skin.

Thirty adult goats were classified at parturition into two body condition score (BCS) groups: BCI (n=16) with a score of 2.7 and BCII (n=14) with a score of 2.0. On the fiftieth day postpartum, oestrus was synchronized by CIDR for 5 days. Upon CIDR removal (Day 0), they received 1 mL of PGF2α IM and mated for 72 hours. Kids were kept with does and weaned at 40 days of age. Blood samples were taken at 0, 1, 4, 8 and 21 days after CIDR removal for progesterone assay. The BCI group showed a greater weight loss compared to the BCII group, and BCS before synchronization was 1.9±0.08 and 1.6±0.07 for the BCI and BCII groups, respectively (P<0.05). The weaning weight of BCI kids was greater when compared to BCII (P<0.001). After CIDR removal, all females were marked and mated. Pregnancy rate was higher in BCI goats (87% vs 36%; P<0.05), as well as prolificacy (1.65 vs 1.25; P<0.05) and twinning rate (0.62 vs 0.25; P<0.05). Progesterone concentration was higher in pregnant does in BCI. A positive relationship was found between progesterone level at CIDR removal and BCS at parturition (0.57; P<0.01), also between progesterone level at 21 days after CIDR removal and BCS at parturition (0.47; P<0.05), or BCS before synchronization (0.51; P<0.05). We conclude that oestrus response to postpartum CIDR synchronization appeared to be slightly dependent on BCS. However, goats with low BCS at oestrus synchronization exhibited a reduction in pregnancy rate.

Mast cells are tissue-resident immune cells that play a key role in inflammation and allergy. Here we show that interaction of mast cells with antibody-targeted cells induces the polarized exocytosis of their granules resulting in a sustained exposure of effector enzymes, such as tryptase and chymase, at the cell–cell contact site. This previously unidentified mast cell effector mechanism, which we name the antibody-dependent degranulatory synapse (ADDS), is triggered by both IgE- and IgG-targeted cells. ADDSs take place within an area of cortical actin cytoskeleton clearance in the absence of microtubule organizing centre and Golgi apparatus repositioning towards the stimulating cell. Remarkably, IgG-mediated degranulatory synapses also occur upon contact with opsonized Toxoplasma gondii tachyzoites resulting in tryptase-dependent parasite death. Our results broaden current views of mast cell degranulation by revealing that human mast cells form degranulatory synapses with antibody-targeted cells and pathogens for dedicated secretion and defence. Mast cells are tissue-resident immune cells important for clearance of parasitic worms but also mediating allergic reactions. Here Joulia et al . show that human mast cells form degranulatory synapses with antibody-targeted cells and pathogens to increase efficiency and minimize off-target effects.

Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin⁺ neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a “neo-self-antigen” specifically in hypothalamic orexin⁺ neurons (called Orex-HA), which were transferred with effector neo-self-antigen–specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin⁺ neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin⁺ neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin⁺ neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy.