A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants.

Microglia are emerging as a key cell type in neurodegenerative diseases, yet human microglia are challenging to study in vitro. We developed an in vitro cell model system composed of human monocyte-derived microglia-like (MDMi) cells that recapitulated key aspects of microglia phenotype and function. We then used this model system to perform an expression quantitative trait locus (eQTL) study examining 94 genes from loci associated with Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We found six loci (CD33, PILRB, NUP160, LRRK2, RGS1, and METTL21B) in which the risk haplotype drives the association with both disease susceptibility and altered expression of a nearby gene (cis-eQTL). In the PILRB and LRRK2 loci, the cis-eQTL was found in the MDMi cells but not in human peripheral blood monocytes, suggesting that differentiation of monocytes into microglia-like cells led to the acquisition of a cellular state that could reveal the functional consequences of certain genetic variants. We further validated the effect of risk haplotypes at the protein level for PILRB and CD33, and we confirmed that the CD33 risk haplotype altered phagocytosis by the MDMi cells. We propose that increased LRRK2 gene expression by MDMi cells could be a functional outcome of rs76904798, a single-nucleotide polymorphism in the LRKK2 locus that is associated with Parkinson's disease.

Evaluation of the implementation of a preventive program for children in brazilian schools / Avaliação da implementação em escolas brasileiras de um programa preventivo para crianças / Evaluación de la implementación en escuelas brasileñas de programa preventivo para niños

Abstract The article discusses the pilot implementation of the evidence-based preventive program Good Behavior Game (GBG) in public schools in four Brazilian cities. GBG is a method for classroom behavior management by teachers, which aims at developing sociability among elementary school students between 6 and 10 years old. The objective of this study was to evaluate the program implementation process, focusing on the acceptability and perceived results by the professionals involved. Mixed methods were used, and data analysis was conducted using triangulation, including questionnaires and semi-structured interviews with 28 teachers, 9 school administrators, and 6 coaches. Data analysis was performed through descriptive and inferential statistics and content analysis, according to the nature of data. GBG had a high acceptance among teachers and school administrators. Professionals highlighted the importance of stimulating teamwork, the systematic use of rewards, and the objectivity of classroom rules. Acceptability was attributed, in large part, to the effectiveness of the strategy for classroom management. Nevertheless, this study highlighted the need of adaptations to better reflect the Brazilian societal and economic context.(AU)

Resumo O artigo discute a implementação piloto do programa preventivo baseado em evidência Good Behavior Game (GBG) em escolas públicas de quatro cidades brasileiras. O GBG é considerado um método para o professor de manejo de comportamentos em sala de aula, visando a construção de sociabilidade entre os estudantes, direcionado para turmas do ensino fundamental, com crianças entre seis e 10 anos. O objetivo deste estudo foi a avaliação do processo de implementação com foco na aceitabilidade e percepção de resultados pelos profissionais envolvidos. Foram utilizados métodos mistos na investigação e triangulação de dados na análise, com base na aplicação de questionários e entrevistas semiestruturadas com 28 professores, nove diretores e seis multiplicadoras do programa. Os dados foram analisados através de estatística descritiva e inferencial ou análise de conteúdo, conforme a natureza do dado. O GBG obteve uma alta aceitação entre professores e diretores. Destacou-se a importância do estímulo ao trabalho em grupo, o uso de elogios como reforçadores, a objetividade das regras assumidas coletivamente. A aceitabilidade foi atribuída, em boa parte, à eficácia de sua estratégia de manejo de sala de aula. Houve indicações da necessidade de adaptações que reflitam o contexto social e econômico brasileiro.(AU)

Resumen El artículo discute la aplicación piloto del programa preventivo basado en evidencia Good Behavior Game (GBG) en escuelas públicas en cuatro ciudades brasileñas. El GBG es considerado un método para maestros direccionados para la gestión de los comportamientos en el aula con miras a la construcción de la sociabilidad entre los estudiantes, dirigido a las clases de la escuela primaria, con niños entre 6 y 10 años. El objetivo del estudio ha sido la evaluación del proceso de implementación con enfoque en la aceptabilidad y los resultados percibidos por los profesionales. Se utilizaron métodos mixtos y el análisis de datos se realizó mediante la triangulación, con base en la aplicación de cuestionarios y entrevistas semi-estructuradas con los 28 maestros, 9 administradores escolares y 6 entrenadores. El análisis de datos se realizó a través de la estadística descriptiva e inferencial y análisis de contenido, de acuerdo con la naturaleza de los datos. GBG tuvo una gran aceptación entre los maestros y administradores escolares. Los profesionales destacaron la importancia de estimular el trabajo en equipo, el uso de alabanza como reforzador, y la objetividad de las normas colectivas. Sin embargo, puso de relieve la necesidad de adaptaciones para reflejar mejor el contexto social y económico de Brasil.(AU)

Evaluation of the Implementation of a Preventive Program for Children in Brazilian Schools / Avaliação da implementação em escolas brasileiras de um programa preventivo para crianças / Evaluación de la Implementación en Escuelas Brasileñas de Programa Preventivo para Niños

Abstract The article discusses the pilot implementation of the evidence-based preventive program Good Behavior Game (GBG) in public schools in four Brazilian cities. GBG is a method for classroom behavior management by teachers, which aims at developing sociability among elementary school students between 6 and 10 years old. The objective of this study was to evaluate the program implementation process, focusing on the acceptability and perceived results by the professionals involved. Mixed methods were used, and data analysis was conducted using triangulation, including questionnaires and semi-structured interviews with 28 teachers, 9 school administrators, and 6 coaches. Data analysis was performed through descriptive and inferential statistics and content analysis, according to the nature of data. GBG had a high acceptance among teachers and school administrators. Professionals highlighted the importance of stimulating teamwork, the systematic use of rewards, and the objectivity of classroom rules. Acceptability was attributed, in large part, to the effectiveness of the strategy for classroom management. Nevertheless, this study highlighted the need of adaptations to better reflect the Brazilian societal and economic context....(AU)

Resumo O artigo discute a implementação piloto do programa preventivo baseado em evidência Good Behavior Game (GBG) em escolas públicas de quatro cidades brasileiras. O GBG é considerado um método para o professor de manejo de comportamentos em sala de aula, visando a construção de sociabilidade entre os estudantes, direcionado para turmas do ensino fundamental, com crianças entre seis e 10 anos. O objetivo deste estudo foi a avaliação do processo de implementação com foco na aceitabilidade e percepção de resultados pelos profissionais envolvidos. Foram utilizados métodos mistos na investigação e triangulação de dados na análise, com base na aplicação de questionários e entrevistas semiestruturadas com 28 professores, nove diretores e seis multiplicadoras do programa. Os dados foram analisados através de estatística descritiva e inferencial ou análise de conteúdo, conforme a natureza do dado. O GBG obteve uma alta aceitação entre professores e diretores. Destacou-se a importância do estímulo ao trabalho em grupo, o uso de elogios como reforçadores, a objetividade das regras assumidas coletivamente. A aceitabilidade foi atribuída, em boa parte, à eficácia de sua estratégia de manejo de sala de aula. Houve indicações da necessidade de adaptações que reflitam o contexto social e econômico brasileiro....(AU)

Resumen El artículo discute la aplicación piloto del programa preventivo basado en evidencia Good Behavior Game (GBG) en escuelas públicas en cuatro ciudades brasileñas. El GBG es considerado un método para maestros direccionados para la gestión de los comportamientos en el aula con miras a la construcción de la sociabilidad entre los estudiantes, dirigido a las clases de la escuela primaria, con niños entre 6 y 10 años. El objetivo del estudio ha sido la evaluación del proceso de implementación con enfoque en la aceptabilidad y los resultados percibidos por los profesionales. Se utilizaron métodos mixtos y el análisis de datos se realizó mediante la triangulación, con base en la aplicación de cuestionarios y entrevistas semi-estructuradas con los 28 maestros, 9 administradores escolares y 6 entrenadores. El análisis de datos se realizó a través de la estadística descriptiva e inferencial y análisis de contenido, de acuerdo con la naturaleza de los datos. GBG tuvo una gran aceptación entre los maestros y administradores escolares. Los profesionales destacaron la importancia de estimular el trabajo en equipo, el uso de alabanza como reforzador, y la objetividad de las normas colectivas. Sin embargo, puso de relieve la necesidad de adaptaciones para reflejar mejor el contexto social y económico de Brasil....(AU)

Trans-pQTL study identifies immune crosstalk between Parkinson and Alzheimer loci.

OBJECTIVE: Given evidence from genetic studies, we hypothesized that there may be a shared component to the role of myeloid function in Parkinson and Alzheimer disease (PD and AD) and assessed whether PD susceptibility variants influenced protein expression of well-established AD-associated myeloid genes in human monocytes. METHODS: We repurposed data in which AD-related myeloid proteins CD33, TREM1, TREM2, TREML2, TYROBP, and PTK2B were measured by flow cytometry in monocytes from 176 participants of the PhenoGenetic Project (PGP) and Harvard Aging Brain Study. Linear regression was used to identify associations between 24 PD risk variants and protein expression. The 2 cohorts were meta-analyzed in a discovery analysis, and the 4 most strongly suggestive results were validated in an independent cohort of 50 PGP participants. RESULTS: We discovered and validated an association between the PD risk allele rs12456492(G) in the RIT2 locus and increased CD33 expression (p joint = 3.50 × 10(-5)) and found strongly suggestive evidence that rs11060180(A) in the CCDC62/HIP1R locus decreased PTK2B expression (p joint = 1.12 × 10(-4)). Furthermore, in older individuals, increased CD33 expression on peripheral monocytes was associated with a greater burden of parkinsonism (p = 0.047), particularly bradykinesia (p = 6.64 × 10(-3)). CONCLUSIONS: We find that the rs12456492 PD risk variant affects expression of AD-associated protein CD33 in peripheral monocytes, which suggests that genetic factors for these 2 diseases may converge to influence overlapping innate immune-mediated mechanisms that contribute to neurodegeneration. Furthermore, the effect of the rs12456492(G) PD risk allele on increased CD33 suggests that the inhibition of certain myeloid functions may contribute to PD susceptibility, as is the case for AD.

CD33 modulates TREM2: convergence of Alzheimer loci.

We used a protein quantitative trait analysis in monocytes from 226 individuals to evaluate cross-talk between Alzheimer loci. The NME8 locus influenced PTK2B and the CD33 risk allele led to greater TREM2 expression. There was also a decreased TREM1/TREM2 ratio with a TREM1 risk allele, decreased TREM2 expression with CD33 suppression and elevated cortical TREM2 mRNA expression with amyloid pathology.

A TREM1 variant alters the accumulation of Alzheimer-related amyloid pathology.

OBJECTIVE: Genome-wide association studies have linked variants in TREM2 (triggering receptor expressed on myeloid cells 2) and TREML2 with Alzheimer disease (AD) and AD endophenotypes. Here, we pursue a targeted analysis of the TREM locus in relation to cognitive decline and pathological features of AD. METHODS: Clinical, cognitive, and neuropathological phenotypes were collected in 3 prospective cohorts on aging (n = 3,421 subjects). Our primary analysis was an association with neuritic plaque pathology. To functionally characterize the associated variants, we used flow cytometry to measure TREM1 expression on monocytes. RESULTS: We provide evidence that an intronic variant, rs6910730(G) , in TREM1, is associated with an increased burden of neuritic plaques (p = 3.7 × 10(-4) ), diffuse plaques (p = 4.1 × 10(-3) ), and Aß density (p = 2.6 × 10(-3) ) as well as an increased rate of cognitive decline (p = 5.3 × 10(-3) ). A variant upstream of TREM2, rs7759295(C) , is independently associated with an increased tau tangle density (p = 4.9 × 10(-4) ), an increased burden of neurofibrillary tangles (p = 9.1 × 10(-3) ), and an increased rate of cognitive decline (p = 2.3 × 10(-3) ). Finally, a cytometric analysis shows that the TREM1 rs6910730(G) allele is associated with decreased TREM1 expression on the surface of myeloid cells (p = 1.7 × 10(-3) ). INTERPRETATION: We provide evidence that 2 common variants within the TREM locus are associated with pathological features of AD and aging-related cognitive decline. Our evidence suggests that these variants are likely to be independent of known AD variants and that they may work through an alteration of myeloid cell function.

Ca(2+) released from calcium alginate gels can promote inflammatory responses in vitro and in vivo.

In general, alginate hydrogels are considered to be biologically inert and are commonly used for biomedical purposes that require minimum inflammation. However, Ca(2+), which is commonly used to crosslink alginate, is a critical second messenger in immune cell signaling, and little has been done to understand its effect on immune cell fate when delivered as a component of alginate gels. We found that dendritic cells (DCs) encapsulated in Ca(2+)-crosslinked alginate (calcium alginate) secreted at least fivefold more of the inflammatory cytokine IL-1ß when compared to DCs encapsulated in agarose and collagen gels, as well as DCs plated on tissue-culture polystyrene (TCPS). Plating cells on TCPS with the alginate polymer could not reproduce these results, whereas culturing DCs on TCPS with increasing concentrations of Ca(2+) increased IL-1ß, MHC class II and CD86 expression in a dose-dependent manner. In agreement with these findings, calcium alginate gels induced greater maturation of encapsulated DCs compared to barium alginate gels. When injected subcutaneously in mice, calcium alginate gels significantly upregulated IL-1ß secretion from surrounding tissue relative to barium alginate gels, and similarly, the inflammatory effects of LPS were enhanced when it was delivered from calcium alginate gels rather than barium alginate gels. These results confirm that the Ca(2+) used to crosslink alginate gels can be immunostimulatory and suggest that it is important to take into account Ca(2+)'s bioactive effects on all exposed cells (both immune and non-immune) when using calcium alginate gels for biomedical purposes. This work may strongly impact the way people use alginate gels in the future as well as provide insights into past work utilizing alginate gels.

New materials for tissue engineering: towards greater control over the biological response.

One goal of tissue engineering is to replace lost or compromised tissue function, and an approach to this is to control the interplay between materials (scaffolds), cells and growth factors to create environments that promote the regeneration of functional tissues and organs. An increased understanding of the chemical signals that direct cell differentiation, migration and proliferation, advances in scaffold design and peptide engineering that allow this signaling to be recapitulated and the development of new materials, such as DNA-based and stimuli-sensitive polymers, have recently given engineers enhanced control over the chemical properties of a material and cell fate. Additionally, the immune system, which is often overlooked, has been shown to play a beneficial role in tissue repair, and future endeavors in material design will potentially expand to include immunomodulation.