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Exosomes (exos) contain molecular cargo of therapeutic and diagnostic value for cancers and other inflammatory diseases, but their therapeutic potential for periodontitis (PD) remains unclear. Dendritic cells (DCs) are the directors of immune response and have been extensively used in immune therapy. We previously reported in a mouse model of PD that custom murine DC-derived exo subtypes could reprogram the immune response toward a bone-sparing or bone-loss phenotype, depending on immune profile. Further advancement of this technology requires the testing of human DC-based exos with human target cells. Our main objective in this study is to test the hypothesis that human monocyte-derived dendritic cell (MoDC)-derived exos constitute a well-tolerated and effective immune therapeutic approach to modulate human target DC and T cell immune responses in vitro. MoDC subtypes were generated with TGFb/IL-10 (regulatory (reg) MoDCs, CD86lowHLA-DRlowPDL1high), E. coli LPS (stimulatory (stim) MoDCs, CD86highHLA-DRhighPDL1low) and buffer (immature (i) MoDCs, CD86lowHLA-DRmedPDL1low). Exosomes were isolated from different MoDC subtypes and characterized. Once released from the secreting cell into the surrounding environment, exosomes protect their prepackaged molecular cargo and deliver it to bystander cells. This modulates the functions of these cells, depending on the cargo content. RegMoDCexos were internalized by recipient MoDCs and induced upregulation of PDL1 and downregulation of costimulatory molecules CD86, HLADR, and CD80, while stimMoDCexos had the opposite influence. RegMoDCexos induced CD25+Foxp3+ Tregs, which expressed CTLA4 and PD1 but not IL-17A. In contrast, T cells treated with stimMoDCexos induced IL-17A+ Th17 T cells, which were negative for immunoregulatory CTLA4 and PD1. T cells and DCs treated with iMoDCexos were immune 'neutral', equivalent to controls. In conclusion, human DC exos present an effective delivery system to modulate human DC and T cell immune responses in vitro. Thus, MoDC exos may present a viable immunotherapeutic agent for modulating immune response in the gingival tissue to inhibit bone loss in periodontal disease.
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Exosomas , Humanos , Ratones , Animales , Antígeno CTLA-4 , Escherichia coli , Células Dendríticas , Antígenos HLA-DR , Inmunidad , Diferenciación Celular , MonocitosRESUMEN
OBJECTIVES: Variation in the external nasal region among human populations has long been proposed in the literature to reflect adaptations to facilitate thermoregulation, air conditioning, and moisture retention in local climates and environments. More specifically, adaptations in populations living in colder climates have often been assumed due to correlational relationships found between variation in the nasal region and climatic variables. Here, we test this hypothesis by applying a quantitative genetics approach based on the Lande model to assess whether variation in the nasal region can be explained by random neutral processes (e.g., genetic drift) or if non-random forces (i.e., adaptation) have contributed significantly to its diversity. MATERIALS AND METHODS: A mixed-sex sample representing 28 population groups from Howells' craniometric dataset were analyzed (n = 2504). Twenty standard measurements were chosen to reflect the external skeletal morphology of the nasal region. We apply statistical tests developed from evolutionary quantitative genetics theory to analyze patterns of within- and between-population divergence under a null hypothesis of genetic drift. RESULTS: This study finds a rejection of genetic drift in all analyses, across tests that involve all 28 populations, exclusively cold-climate populations, and with cold-climate populations excluded, indicating that non-random evolutionary forces have contributed significantly to variation in the nasal region overall. DISCUSSION: These results show that nasal region adaptation is not exclusive to cold-climate populations, which have often been implicated in the literature to drive nasal variation, instead suggesting that the propensity for adaptation in the nasal region is shared among all human populations.
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Evolución Biológica , Clima , Cefalometría , Flujo Genético , Humanos , Nariz/anatomía & histologíaRESUMEN
This cross-sectional study examines the differences in cortical volume and gray-to-white matter contrast (GWC) in first episode schizophrenia patients (SCZ) compared to healthy control participants (HC) and in SCZ patients as a function of exposure to second generation antipsychotic medication. We hypothesize 1) SCZ exhibit regionally lower cortical volumes relative to HCs, 2) cortical volume will be greater with longer exposure to second generation antipsychotics prior to the MRI scan, and 3) lower GWC with longer exposure to second generation antipsychotics prior to the MRI scan, suggesting more blurring from greater intracortical myelin. To accomplish this, MRI scans from 71 male SCZ patients treated with second generation oral risperidone and 42 male HCs were examined. 3D T1-weighted MPRAGE images collected at 1.5T were used to estimate cortical volume and GWC by sampling signal intensity at 30% within the cortical ribbon. Average cortical volume and GWC were calculated and compared between SCZ and HC. Cortical volume and GWC in SCZ patients were correlated with duration of medication exposure for the time period prior to the scan. First-episode SCZ patients had significantly lower cortical volume compared to HCs in bilateral temporal, superior and rostral frontal, postcentral gyral, and parahippocampal regions. In SCZ patients, greater cortical volume was associated with (log-transformed) duration of second-generation antipsychotic medication exposure in bilateral precuneus, right lingual, and right superior parietal regions. Lower GWC was correlated with longer duration of medication exposure bilaterally in the superior frontal lobes. In summary, second generation antipsychotics may increase cortical volume and decrease GWC in first episode SCZ patients.
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Antipsicóticos , Esquizofrenia , Sustancia Blanca , Antipsicóticos/uso terapéutico , Estudios Transversales , Sustancia Gris/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/tratamiento farmacológico , Sustancia Blanca/diagnóstico por imagenRESUMEN
Stroke is the leading cause of adult disability worldwide, with up to two-thirds of individuals experiencing long-term disabilities. Large-scale neuroimaging studies have shown promise in identifying robust biomarkers (e.g., measures of brain structure) of long-term stroke recovery following rehabilitation. However, analyzing large rehabilitation-related datasets is problematic due to barriers in accurate stroke lesion segmentation. Manually-traced lesions are currently the gold standard for lesion segmentation on T1-weighted MRIs, but are labor intensive and require anatomical expertise. While algorithms have been developed to automate this process, the results often lack accuracy. Newer algorithms that employ machine-learning techniques are promising, yet these require large training datasets to optimize performance. Here we present ATLAS (Anatomical Tracings of Lesions After Stroke), an open-source dataset of 304 T1-weighted MRIs with manually segmented lesions and metadata. This large, diverse dataset can be used to train and test lesion segmentation algorithms and provides a standardized dataset for comparing the performance of different segmentation methods. We hope ATLAS release 1.1 will be a useful resource to assess and improve the accuracy of current lesion segmentation methods.
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Encéfalo/diagnóstico por imagen , Encéfalo/patología , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/patología , Adulto , Algoritmos , Humanos , Imagen por Resonancia Magnética , NeuroimagenRESUMEN
Research on mathematics education has shown that learners' actions can influence how they think and vice versa. Much of this work has been rooted in the use of manipulatives, gestures, and body movements. Our article dissects the mechanisms that underscore the impact of embodied activities and applies this lens to explore how to harness the affordances of new technology to enhance mathematical thinking. This is especially crucial given the increasing accessibility of technology-such as digital touch devices, 3D printers, and location sensors-for constructing embodied experiences. Providing guidance for incorporating those tools, we focus on the role that embodied cognition can play in communicating mathematical concepts as well as in allowing learners to experiment and evolve their ideas. To inspire future integration of theory in the development of technologically enhanced embodied mathematics experiences, we provide examples of how this can be done. Finally, we outline future directions in the areas of design, implementation, and assessment of embodied learning of mathematics.
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Anatomical, molecular, and physiological interactions between astrocytes and neuronal synapses regulate information processing in the brain. The fruit fly Drosophila melanogaster has become a valuable experimental system for genetic manipulation of the nervous system and has enormous potential for elucidating mechanisms that mediate neuron-glia interactions. Here, we show the first electrophysiological recordings from Drosophila astrocytes and characterize their spatial and physiological relationship with particular synapses. Astrocyte intrinsic properties were found to be strongly analogous to those of vertebrate astrocytes, including a passive current-voltage relationship, low membrane resistance, high capacitance, and dye-coupling to local astrocytes. Responses to optogenetic stimulation of glutamatergic premotor neurons were correlated directly with anatomy using serial electron microscopy reconstructions of homologous identified neurons and surrounding astrocytic processes. Robust bidirectional communication was present: neuronal activation triggered astrocytic glutamate transport via excitatory amino acid transporter 1 (Eaat1), and blocking Eaat1 extended glutamatergic interneuron-evoked inhibitory postsynaptic currents in motor neurons. The neuronal synapses were always located within 1 µm of an astrocytic process, but none were ensheathed by those processes. Thus, fly astrocytes can modulate fast synaptic transmission via neurotransmitter transport within these anatomical parameters. J. Comp. Neurol. 524:1979-1998, 2016. © 2016 Wiley Periodicals, Inc.
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Astrocitos/fisiología , Sistema Nervioso Central/citología , Proteínas de Drosophila/metabolismo , Neuronas/fisiología , Sinapsis/fisiología , Factores de Transcripción/metabolismo , Animales , Animales Modificados Genéticamente , Ácido Aspártico/farmacología , Astrocitos/ultraestructura , Cloruro de Cadmio/farmacología , Moléculas de Adhesión Celular Neuronal/metabolismo , Sistema Nervioso Central/fisiología , Sistema Nervioso Central/ultraestructura , Colina O-Acetiltransferasa/metabolismo , Drosophila , Proteínas de Drosophila/antagonistas & inhibidores , Proteínas de Drosophila/genética , Transportador 1 de Aminoácidos Excitadores/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/genética , Larva , Locomoción/genética , Red Nerviosa/fisiología , Red Nerviosa/ultraestructura , Neuronas/ultraestructura , Bloqueadores de los Canales de Sodio/farmacología , Sinapsis/genética , Sinapsis/ultraestructura , Tetrodotoxina/farmacología , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismoRESUMEN
This study uses student panel data to examine the association between Algebra placement and student motivation for mathematics. Changes in achievement goals, expectancy, and task value for students in eighth grade Algebra are compared with those of peers placed in lower-level mathematics courses (N = 3,306). In our sample, students placed in Algebra reported an increase in performance-avoidance goals as well as decreases in academic self-efficacy and task value. These relations were attenuated for students who had high mathematics achievement prior to Algebra placement. Whereas all students reported an overall decline in performance-approach goals over the course of eighth grade, previously high-achieving students reported an increase in these goals. Lastly, previously high-achieving students reported an increase in mastery goals. These findings suggest that while previously high-achieving students may benefit motivationally from eighth grade Algebra placement, placing previously average- and low-performing students in Algebra can potentially undermine their motivation for mathematics.
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The effectiveness of less versus more intensive psychological therapies in reducing suicidal behavior and depression in suicidal patients with borderline personality disorder (BPD) was examined. Electronic databases were searched. Trials were separated into less versus more intensive therapies. Suicidal acts and depression outcome data were assessed. Six trials met search criteria (cognitive-behavioral therapy for personality disorder, mentalization-based therapy, dialectical behavior therapy). Seven measures of suicidal acts and two measures of depression were used in studies. Both less and more intensive therapies report significant decreases in suicidal behaviors. Apart from one small trial, both less and more intensive therapies report decreases in depression with no differences between therapies and control conditions. Two follow-up studies showed that reductions in suicidal behavior and depression are maintained over time. The authors conclude that both less and more intensive therapies are effective in treating depression and suicidal behaviors in patients with BPD. Clinicians should deliver the least intensive interventions that will provide these significant health gains.
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Trastorno de Personalidad Limítrofe/terapia , Depresión/prevención & control , Psicoterapia/métodos , Suicidio/psicología , Trastorno de Personalidad Limítrofe/psicología , Humanos , Resultado del TratamientoRESUMEN
This study investigated the relative contribution of the Big 5 personality factors and alcohol metacognitions in predicting weekly levels of alcohol use in binge drinking university students. No research to date has investigated whether either of these constructs predicts levels of weekly alcohol use in binge drinkers. A sample of university students (n=142) who were classified as binge drinkers were administered the following self-report instruments: NEO-Five Factor Inventory (NEO-FFI; Costa & McCrae, 1992), Positive Alcohol Metacognitions Scale (PAMS; Spada & Wells, 2008), Negative Alcohol Metacognitions Scale (NAMS; Spada & Wells, 2008), and Khavari Alcohol Test (KAT; Khavari & Farber, 1978). Pearson product-moment correlations showed that weekly levels of alcohol use were negatively correlated with agreeableness and conscientiousness and positively correlated with positive alcohol metacognitions about cognitive self-regulation, negative alcohol metacognitions about uncontrollability and negative alcohol metacognitions about cognitive harm. A hierarchical regression analysis revealed that conscientiousness and positive alcohol metacognitions about cognitive self-regulation were the only two significant predictors of weekly levels of alcohol use when controlling for gender. These findings show that being male, low on conscientiousness and high on positive alcohol metacognitions about cognitive self-regulation raises the risk for increased weekly levels of alcohol use in binge drinking university students. The implications of these findings are discussed.