The Toll-Like Receptor Gene Family Is Integrated into Human DNA Damage and p53 Networks

In recent years the functions that the p53 tumor suppressor plays in human biology have been greatly extended beyond “guardian of the genome.” Our studies of promoter response element sequences targeted by the p53 master regulatory transcription factor suggest a general role for this DNA damage and stress-responsive regulator in the control of human Toll-like receptor (TLR) gene expression. The TLR gene family mediates innate immunity to a wide variety of pathogenic threats through recognition of conserved pathogen-associated molecular motifs. Using primary human immune cells, we have examined expression of the entire TLR gene family following exposure to anti-cancer agents that induce the p53 network. Expression of all TLR genes, TLR1 to TLR10, in blood lymphocytes and alveolar macrophages from healthy volunteers can be induced by DNA metabolic stressors. However, there is considerable inter-individual variability. Most of the TLR genes respond to p53 via canonical as well as noncanonical promoter binding sites. Importantly, the integration of the TLR gene family into the p53 network is unique to primates, a recurrent theme raised for other gene families in our previous studies. Furthermore, a polymorphism in a TLR8 response element provides the first human example of a p53 target sequence specifically responsible for endogenous gene induction. These findings—demonstrating that the human innate immune system, including downstream induction of cytokines, can be modulated by DNA metabolic stress—have many implications for health and disease, as well as for understanding the evolution of damage and p53 responsive networks

Identification of Stage-Specific Breast Markers using Quantitative Proteomics

YesMatched healthy and diseased tissues from breast cancer patients were analyzed by quantitative proteomics. By comparing proteomic profiles of fibroadenoma (benign tumors, three patients), DCIS (noninvasive cancer, three patients), and invasive ductal carcinoma (four patients), we identified protein alterations that correlated with breast cancer progression. Three 8-plex iTRAQ experiments generated an average of 826 protein identifications, of which 402 were common. After excluding those originating from blood, 59 proteins were significantly changed in tumor compared with normal tissues, with the majority associated with invasive carcinomas. Bioinformatics analysis identified relationships between proteins in this subset including roles in redox regulation, lipid transport, protein folding, and proteasomal degradation, with a substantial number increased in expression due to Myc oncogene activation. Three target proteins, cofilin-1 and p23 (increased in invasive carcinoma) and membrane copper amine oxidase 3 (decreased in invasive carcinoma), were subjected to further validation. All three were observed in phenotype-specific breast cancer cell lines, normal (nontransformed) breast cell lines, and primary breast epithelial cells by Western blotting, but only cofilin-1 and p23 were detected by multiple reaction monitoring mass spectrometry analysis. All three proteins were detected by both analytical approaches in matched tissue biopsies emulating the response observed with proteomics analysis. Tissue microarray analysis (361 patients) indicated cofilin-1 staining positively correlating with tumor grade and p23 staining with ER positive status; both therefore merit further investigation as potential biomarkers.Cyprus Research Promotion Foundation, Yorkshire Cancer Researc

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

Modulation of immune responses by the tumor suppressor p53

The commonly held view of the tumor suppressor p53 as a regulator of cell proliferation, apoptosis and senescence has expanded greatly in recent years to cover many biological processes as well as external and internal stress responses. Since the discovery over 30 years ago of p53 as a cellular protein that co-precipitates with the large T antigen of Simian Virus SV40, there has been an intertwining of p53 activities with immune-related processes, especially as relates to cancer. A variety of interactions between the p53 and the immune stress systems are currently being addressed that suggest opportunities to utilize p53 in modulating immunological activities. Here, we discuss those interactions along with implications for human disease

Estratégias de comunicação em situação poliádica de creche Strategies for communicating in polivalent situations at day care

Tendo em vista a importância das experiências iniciais, em termos de responsividade e sincronicidade nas interações com o meio, com amplas repercussões nos terrenos cognitivo, social e afetivo, o presente trabalho objetivou investigar as possibilidades da creche como contexto interacional. 62 crianças de um a três anos, de cinco creches diferentes, metade delas proveniente de creches privadas e as demais de creches públicas, foram observadas em seus ambientes naturais de brinquedo, nas creches, em três sessões de dez minutos cada, tomadas em dias diferentes. Amostras de episódios interativos entre adultos e crianças foram examinados qualitativamente, buscando identificar os parceiros das interações e os modos pelos quais criança e adultos situam-se no conjunto das interações. Os resultados dessa análise sugeriram que o adulto, além das esperadas estratégias de comunicação individual ou coletiva, emprega comumente uma terceira estratégia básica de comunicação, aqui denominada comunicação articulada, com alternância de alvos e articulação, inclusive temática, entre os alvos. Nesse padrão, o adulto estende as interações que ocorrem com um indivíduo para outros, amplificando o episódio interativo, criando inter-relações entre temas e indivíduos. Esses resultados são discutidos em termos da inadequação da oposição situação diádica versus poliádica, que costuma ser empregada para comparar os contextos de criação em ambientes familiar ou coletivo.<br>Considering the importance of early experiences, particularly regarding responsiveness and synchrony in the interactions with the environment, with important effects on the cognitive, affective and social areas, this study aimed to search the day-care-centers possibilities as interactional contexts. 62 children aged 1 to 3 years old, from 5 different day-care centers, half of them from private and the others from public day-care centers, were observed at their natural play settings, in three sessions of 10 minutes each, obtained in different days. Samples of interactive episodes between adults and children were qualitatively examined, aiming to identify the interactional partners and the ways through which children and adults set themselves in the whole interactional pattern. The results of this analysis suggest that the adult, besides the expected strategies of individual and collective communication, use ordinarily a third basic communication strategy, called articuled communication, with thematic and other forms of alternation between the targets. In this pattern, the adult extends the interactions that occur with an individual to others, amplifying the interactive episode, creating links between themes and individuals. These results are discussed in terms of the inadequacy of the opposition between dyadic versus polyadic situations, that is generally used to compare the rearing contexts in family and collective environments