Mechanisms of tissue compartmentalization in human T cells

Mechanisms for human memory T cell differentiation and maintenance have predominantly been inferred from studies of peripheral blood, though the majority of T cells reside in lymphoid and non-lymphoid sites. Studies in mice have shown that memory T cells in non-lymphoid sites provide superior protection to pathogens compared to those in blood, defining a subset known as tissue-resident memory T cells (TRM), with emerging roles in lymphoid sites. There are many key unknown aspects of TRM biology in human tissues including if TRM have superior functional abilities, the mechanisms for maintenance of TRM in lymphoid and non-lymphoid sites, and the relatedness of tissue and blood localized T cell subsets. Through a collaboration with the local organ procurement agency, we obtained samples from >15 tissue sites from healthy organ donors of all ages. We analyzed CD8+ T cells in diverse sites and found the majority of TRM cells in lymph nodes (LNs) display an increased proliferative capacity, increased expression of TCF-1, and decreased turnover compared to TRM and effector memory (TEM) cells in other sites including blood, bone marrow (BM), spleen and lung. Further, we identified that exposure to type 1 interferons results in increased downregulation of TCF-1 expression during cell divisions driven by T cell receptor (TCR) stimulation. We investigated the relatedness of CD4+ and CD8+ T cell subsets, including central memory (TCM), effector memory (TEM), TRM, and terminal effectors (TEMRA) by sequencing TCR rearrangements. From diversity analysis of TCR repertoires we found that effector and memory subsets are maintained in a hierarchy from most to least diverse (TCM > TEM and TRM > TEMRA) that is largely conserved across tissues and CD4+ and CD8+ T cell lineages. Overlap analysis revealed the low and high relatedness of TCM and TEMRA cells respectively and this was highly conserved across tissues; in contrast, we found the relatedness of TEM and TRM was more dynamic across tissues. Together, these findings have implications for immune monitoring and modulation, highlighting that lymph nodes may function as reservoirs for long-lived memory T cells with high functional capacity; additionally, we identify cell extrinsic signals that regulate tissue-specific maintenance of T cell memory in lymph node sites

Animals Out of the Clouds

School of Art and Design: Integrative Project ThesisArt and Design, School ofUniversity of MichiganUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/60507/1/IPThesis_Miron.pd

Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites

Tissue-resident memory T cells (TRMs) in mice mediate optimal protective immunity to infection and vaccination, while in humans, the existence and properties of TRMs remain unclear. Here, we use a unique human tissue resource to determine whether human tissue memory T cells constitute a distinct subset in diverse mucosal and lymphoid tissues. We identify a core transcriptional profile within the CD69+ subset of memory CD4+ and CD8+ T cells in lung and spleen that is distinct from that of CD69− TEM cells in tissues and circulation and defines human TRMs based on homology to the transcriptional profile of mouse CD8+ TRMs. Human TRMs in diverse sites exhibit increased expression of adhesion and inhibitory molecules, produce both pro-inflammatory and regulatory cytokines, and have reduced turnover compared with circulating TEM, suggesting unique adaptations for in situ immunity. Together, our results provide a unifying signature for human TRM and a blueprint for designing tissue-targeted immunotherapies

Evaluation of territorialities in social housing : a case study in the Program Integrado Entrada da Cidade (PIEC)

No contexto dos empreendimentos habitacionais de interesse social (EHIS), expressões de territorialização dos usuários podem ser manifestadas através de apropriações no ambiente construído. Esse processo de apropriação do espaço pelo usuário indicaria a construção de um sentimento de pertencimento, que pode ser concretamente expressado por meio de alterações físicas. Tais apropriações também podem indicar riscos ao alcance dos objetivos esperados pelos programas habitacionais, tais como: (i) conflitos na vizinhança; (ii) falta de conforto e habitabilidade na habitação; (ii) falta de segurança nas áreas de uso coletivo e; (iv) falta de saneamento nos loteamentos. O objetivo deste artigo é identificar e mapear as territorialidades expressadas como apropriações concretas através de alterações físicas nos espaços públicos e privados de três empreendimentos habitacionais de interesse social pertencentes ao Programa Integrado Entrada da Cidade (PIEC). O estudo empírico, envolveu a construção de um questionário, observações in loco, planejamento amostral, coleta e análise de dados. Para as análises dos dados foram utilizadas técnicas estatísticas descritivas e mapeamentos gráficos. Dentre as principais contribuições desta pesquisa estão a identificação, a categorização e o mapeamento de formas de territorialidade existentes nos EHIS investigados. Ainda, as territorialidades analisadas em conjunto com o percentual de permanência dos moradores indicaram novos caminhos para a compreensão dos impactos sobre a qualidade de vida desses usuários, bem como para o monitoramento dos resultados dos investimentos em habitação social no Brasil.Within the context of social housing (EHIS), users may express territorialization through appropriations in the built environment. This process of appropriation of space by the user indicates the construction of a sense of belonging, which can be concretely expressed through physical changes. These appropriations may also indicate risks to achieving the objectives expected by housing programs, such as: (i) conflicts in the neighborhood; (ii) lack of comfort and livability in housing; (iii) lack of security in common areas, and; (iv) lack of sanitation in housing allotments. This article aims to identify and map the territorialities expressed as concrete appropriations through physical changes in public and private spaces in three social housing estates belonging to the Programa Integrado Entrada da Cidade (PIEC). The empirical study consisted in the elaboration of a questionnaire, observations “in loco”, sample design, and data collection and analysis. For data analysis, it was used descriptive statistics techniques and graphic mappings. The main contributions of this research are the identification, categorization, and mapping of the different forms of territoriality existent in the EHIS investigated. Moreover, the territorialities analyzed along with the percentage of permanence of the residents indicated new ways of comprehending the impacts on the quality of life of these users, as well as for monitoring the results of investments in social housing in Brazil

Avaliação das territorialidades em empreendimentos habitacionais de interesse social: estudo de caso no Programa Integrado Entrada da Cidade (PIEC)

Within the context of social housing (EHIS), users may express territorialization through appropriations in the built environment. This process of appropriation of space by the user indicates the construction of a sense of belonging, which can be concretely expressed through physical changes. These appropriations may also indicate risks to achieving the objectives expected by housing programs, such as: (i) conflicts in the neighborhood; (ii) lack of comfort and livability in housing; (iii) lack of security in common areas, and; (iv) lack of sanitation in housing allotments. This article aims to identify and map the territorialities expressed as concrete appropriations through physical changes in public and private spaces in three social housing estates belonging to the Programa Integrado Entrada da Cidade (PIEC). The empirical study consisted in the elaboration of a questionnaire, observations “in loco”, sample design, and data collection and analysis. For data analysis, it was used descriptive statistics techniques and graphic mappings. The main contributions of this research are the identification, categorization, and mapping of the different forms of territoriality existent in the EHIS investigated. Moreover, the territorialities analyzed along with the percentage of permanence of the residents indicated new ways of comprehending the impacts on the quality of life of these users, as well as for monitoring the results of investments in social housing in Brazil.Keywords: territorialities, social housing (EHIS), Programa Integrado Entrada da Cidade (PIEC).No contexto dos empreendimentos habitacionais de interesse social (EHIS), expressões de territorialização dos usuários podem ser manifestadas através de apropriações no ambiente construído. Esse processo de apropriação do espaço pelo usuário indicaria a construção de um sentimento de pertencimento, que pode ser concretamente expressado por meio de alterações físicas. Tais apropriações também podem indicar riscos ao alcance dos objetivos esperados pelos programas habitacionais, tais como: (i) conflitos na vizinhança; (ii) falta de conforto e habitabilidade na habitação; (ii) falta de segurança nas áreas de uso coletivo e; (iv) falta de saneamento nos loteamentos. O objetivo deste artigo é identificar e mapear as territorialidades expressadas como apropriações concretas através de alterações físicas nos espaços públicos e privados de três empreendimentos habitacionais de interesse social pertencentes ao Programa Integrado Entrada da Cidade (PIEC). O estudo empírico, envolveu a construção de um questionário, observações in loco, planejamento amostral, coleta e análise de dados. Para as análises dos dados foram utilizadas técnicas estatísticas descritivas e mapeamentos gráficos. Dentre as principais contribuições desta pesquisa estão a identificação, a categorização e o mapeamento de formas de territorialidade existentes nos EHIS investigados. Ainda, as territorialidades analisadas em conjunto com o percentual de permanência dos moradores indicaram novos caminhos para a compreensão dos impactos sobre a qualidade de vida desses usuários, bem como para o monitoramento dos resultados dos investimentos em habitação social no Brasil.Palavras-chave: territorialidades, empreendimentos habitacionais de interesse social (EHIS), Programa Integrado Entrada da Cidade (PIEC)

A Conserved Role for Syndecan Family Members in the Regulation of Whole-Body Energy Metabolism

Syndecans are a family of type-I transmembrane proteins that are involved in cell-matrix adhesion, migration, neuronal development, and inflammation. Previous quantitative genetic studies pinpointed Drosophila Syndecan (dSdc) as a positional candidate gene affecting variation in fat storage between two Drosophila melanogaster strains. Here, we first used quantitative complementation tests with dSdc mutants to confirm that natural variation in this gene affects variability in Drosophila fat storage. Next, we examined the effects of a viable dSdc mutant on Drosophila whole-body energy metabolism and associated traits. We observed that young flies homozygous for the dSdc mutation had reduced fat storage and slept longer than homozygous wild-type flies. They also displayed significantly reduced metabolic rate, lower expression of spargel (the Drosophila homologue of PGC-1), and reduced mitochondrial respiration. Compared to control flies, dSdc mutants had lower expression of brain insulin-like peptides, were less fecund, more sensitive to starvation, and had reduced life span. Finally, we tested for association between single nucleotide polymorphisms (SNPs) in the human SDC4 gene and variation in body composition, metabolism, glucose homeostasis, and sleep traits in a cohort of healthy early pubertal children. We found that SNP rs4599 was significantly associated with resting energy expenditure (P = 0.001 after Bonferroni correction) and nominally associated with fasting glucose levels (P = 0.01) and sleep duration (P = 0.044). On average, children homozygous for the minor allele had lower levels of glucose, higher resting energy expenditure, and slept shorter than children homozygous for the common allele. We also observed that SNP rs1981429 was nominally associated with lean tissue mass (P = 0.035) and intra-abdominal fat (P = 0.049), and SNP rs2267871 with insulin sensitivity (P = 0.037). Collectively, our results in Drosophila and humans argue that syndecan family members play a key role in the regulation of body metabolism

Creative destruction in science

Drawing on the concept of a gale of creative destruction in a capitalistic economy, we argue that initiatives to assess the robustness of findings in the organizational literature should aim to simultaneously test competing ideas operating in the same theoretical space. In other words, replication efforts should seek not just to support or question the original findings, but also to replace them with revised, stronger theories with greater explanatory power. Achieving this will typically require adding new measures, conditions, and subject populations to research designs, in order to carry out conceptual tests of multiple theories in addition to directly replicating the original findings. To illustrate the value of the creative destruction approach for theory pruning in organizational scholarship, we describe recent replication initiatives re-examining culture and work morality, working parents\u2019 reasoning about day care options, and gender discrimination in hiring decisions. Significance statement It is becoming increasingly clear that many, if not most, published research findings across scientific fields are not readily replicable when the same method is repeated. Although extremely valuable, failed replications risk leaving a theoretical void\u2014 reducing confidence the original theoretical prediction is true, but not replacing it with positive evidence in favor of an alternative theory. We introduce the creative destruction approach to replication, which combines theory pruning methods from the field of management with emerging best practices from the open science movement, with the aim of making replications as generative as possible. In effect, we advocate for a Replication 2.0 movement in which the goal shifts from checking on the reliability of past findings to actively engaging in competitive theory testing and theory building. Scientific transparency statement The materials, code, and data for this article are posted publicly on the Open Science Framework, with links provided in the article