Developmental scientists have long described mid-adolescents' emerging capacities to make deep meaning about the social world and self, here called transcendent thinking, as a hallmark developmental ...stage. In this 5-years longitudinal study, sixty-five 14-18 years-old youths' proclivities to grapple psychologically with the ethical, systems-level and personal implications of social stories, predicted future increases in the coordination of two key brain networks: the default-mode network, involved in reflective, autobiographical and free-form thinking, and the executive control network, involved in effortful, focused thinking; findings were independent of IQ, ethnicity, and socioeconomic background. This neural development predicted late-adolescent identity development, which predicted young-adult self-liking and relationship satisfaction, in a developmental cascade. The findings reveal a novel predictor of mid-adolescents' neural development, and suggest the importance of attending to adolescents' proclivities to engage agentically with complex perspectives and emotions on the social and personal relevance of issues, such as through civically minded educational approaches.
The concept of resilience has experienced extraordinary development since the 1970s. Resilience is now an integral part of human society and has become a hot topic in different research domains. As ...an interdisciplinary discipline, resilience science is supported by multidisciplinary knowledge. Although research and practical work of resilience have been developed significantly, it is still unclear that how far resilience science has been progressed as a scientific discipline. In order to reveal the connotation and knowledge structure of resilience science, we systematically reviewed classic publications on resilience and compared its definitions and related research in different discipline domains. The evolution trend of resilience science was quantitatively analyzed to identify its knowledge foundation, geographic distribution, academic community, and collaboration structure. This analysis revealed the knowledge structure and development path of resilience science for future researchers. The results showed that the publications of resilience have been explosively increased since the 2000s. The developed countries made sound contributions to the research of resilience science, and China also presents a significant growth trend in this area. The collaborative relationship is becoming closer across research institutions and scholars. The research topics of resilience have been changing in the latest 30 years. The results reveal important highlights and future research directions of resilience science on academic domains including definition of resilience, measurement methods of network resilience, and mechanisms to forming resilient status. Moreover, this study will help researchers in resilience science for future collaboration and work.
The diversities of stakeholder concerns and intricate interdependencies between stakeholder concerns are important factors adding complexities to major public engineering projects (MEPs). Using case ...study and network-theory based analysis in a large reclamation project, this paper investigated the key stakeholder concerns and concern interdependencies of MEPs, and how they bring major challenges confronted by stakeholders. The network analysis identifies five major challenges of the case: “applying highly advanced and complex construction technology”, “mitigating project disruptions to the environment and marine ecology”, “conducting public and community consultation during construction phase”, “site constraints due to nearby air and marine traffic”, and “meeting government standard on the quality of new materials and equipment”. Recommendations are provided to alleviate these problems for future MEPs. This paper contributes to a new angle, the network perspective, of analyzing stakeholder concern interdependencies and their practical implications on MEPs. The findings provide useful insights on common pitfalls of MEPs.
•Stakeholder concerns and their interdependencies in MEPs are analyzed from a network perspective.•A case study of large reclamation project is conducted to illustrate the network analysis.•Five major challenges confronted by stakeholders in the case have been identified.•Recommendations are provided to alleviate these problems for future MEPs.
Previous research on risks in complex green building projects has been mainly focused on what the risks are and how they may impact on project objectives. Such studies have tended toward an inward ...looking perspective that treats risks in isolation from one another. In reality, most risks are interrelated and associated with internal or external project stakeholders. To address this research gap, this current research developed a Social Network Analysis (SNA) based stakeholder-associated risk analysis method to assess and analyse the risks and their interactions in complex green building projects. A case study was conducted to highlight the green-specific risks and their profiles, together with the proposed mitigation actions. The research results presented in this paper may broaden researchers and construction professionals' awareness of influential risks in green building projects and enhance their ability to perceive, understand, assess, and mitigate the risks in an effective and efficient way; thereby achieving higher performance in strategic risk management and stakeholder communication in green building project management.
•Research paradigms shift from linear impact analysis to network perspective.•We develop a social network method for analysing stakeholder-associated risks.•Internal stakeholders, media and assessor/certifier play more important roles in green building.•Ethical/reputational risks are considered more significant in green building development.
The NLRP3 inflammasome has an important function in inflammation by promoting the processing of pro-IL-1β and pro-IL-18 to their mature bioactive forms, and by inducing cell death via pyroptosis. ...Here we show a critical function of the E3 ubiquitin ligase Pellino2 in facilitating activation of the NLRP3 inflammasome. Pellino2-deficient mice and myeloid cells have impaired activation of NLRP3 in response to toll-like receptor priming, NLRP3 stimuli and bacterial challenge. These functions of Pellino2 in the NLRP3 pathway are dependent on Pellino2 FHA and RING-like domains, with Pellino2 promoting the ubiquitination of NLRP3 during the priming phase of activation. We also identify a negative function of IRAK1 in the NLRP3 inflammasome, and describe a counter-regulatory relationship between IRAK1 and Pellino2. Our findings reveal a Pellino2-mediated regulatory signaling system that controls activation of the NLRP3 inflammasome.
Tissues and organs provide the structural and biochemical landscapes upon which microbial pathogens and commensals function to regulate health and disease. While flat two-dimensional (2-D) monolayers ...composed of a single cell type have provided important insight into understanding host-pathogen interactions and infectious disease mechanisms, these reductionist models lack many essential features present in the native host microenvironment that are known to regulate infection, including three-dimensional (3-D) architecture, multicellular complexity, commensal microbiota, gas exchange and nutrient gradients, and physiologically relevant biomechanical forces (e.g., fluid shear, stretch, compression). A major challenge in tissue engineering for infectious disease research is recreating this dynamic 3-D microenvironment (biological, chemical, and physical/mechanical) to more accurately model the initiation and progression of host-pathogen interactions in the laboratory. Here we review selected 3-D models of human intestinal mucosa, which represent a major portal of entry for infectious pathogens and an important niche for commensal microbiota. We highlight seminal studies that have used these models to interrogate host-pathogen interactions and infectious disease mechanisms, and we present this literature in the appropriate historical context. Models discussed include 3-D organotypic cultures engineered in the rotating wall vessel (RWV) bioreactor, extracellular matrix (ECM)-embedded/organoid models, and organ-on-a-chip (OAC) models. Collectively, these technologies provide a more physiologically relevant and predictive framework for investigating infectious disease mechanisms and antimicrobial therapies at the intersection of the host, microbe, and their local microenvironments.
This research aims to model the interactive networks of the risks associated with different stakeholders in green building projects and to gain an understanding of the key risk networks. Case studies ...of green star accredited office building projects were undertaken in China and Australia. Case data were collected through focused group workshops, face-to-face interviews and desktop studies, and analysed by using social network analysis methods. The results show that while reputation risk is important in both countries, the ethical risk of ‘assessment experience and fairness’ has been highlighted as crucial in the Chinese context. The results further show that government plays an important role in improving the societies' knowledge and awareness on green technology uptake in China. The social network analysis method in this research improves the effectiveness and accuracy of stakeholder and risk analysis by demystifying the social complexity which is usually overlooked in traditional linear risk impact analysis.
•Model the interactive networks of the risks associated with different stakeholders in green building projects•Identify the critical risks and associated stakeholders by using social network analysis methods.•Social network analysis method improves the accuracy of stakeholder and risk analysis by demystifying the social complexity.•Highlight the critical risks and stakeholders in Australia and China, and explain the reasons underlining the distinction.
Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason for the failure of such ...therapies is that genomic profiling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed significant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifications not detected in PT sampling. Lastly, we profiled paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profiling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profiling to enhance selection of therapy.
We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profiling of metastatic lesions and/or cfDNA should be systematically evaluated.
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Autophagy cargo recognition and clearance are essential for intracellular protein quality control. SQSTM1/p62 sequesters intracellular aberrant proteins and mediates cargo delivery for their ...selective autophagic degradation. The formation of p62 non-membrane-bound liquid compartments is critical for its function as a cargo receptor. The regulation of p62 phase separation/condensation has yet been poorly characterised. Using an unbiased yeast two-hybrid screening and complementary approaches, we found that DAXX physically interacts with p62. Cytoplasmic DAXX promotes p62 puncta formation. We further elucidate that DAXX drives p62 liquid phase condensation by inducing p62 oligomerisation. This effect promotes p62 recruitment of Keap1 and subsequent Nrf2-mediated stress response. The present study suggests a mechanism of p62 phase condensation by a protein interaction, and indicates that DAXX regulates redox homoeostasis, providing a mechanistic insight into the prosurvival function of DAXX.
Both the DNA damage response (DDR) and the mitotic checkpoint are critical for the maintenance of genomic stability. Among proteins involved in these processes, the ataxia–telangiectasia mutated ...(ATM) kinase is required for both activation of the DDR and the spindle assembly checkpoint (SAC). In mitosis without DNA damage, the enzymatic activity of ATM is enhanced; however, substrates of ATM in mitosis are unknown. Using stable isotope labeling of amino acids in cell culture mass spectrometry analysis, we identified a number of proteins that can potentially be phosphorylated by ATM during mitosis. This list is highly enriched in proteins involved in cell cycle regulation and the DDR. Among them, we further validated that ATM phosphorylated budding uninhibited by benzimidazoles 3 (Bub3), a major component of the SAC, on serine 135 (Ser135) both in vitro and in vivo. During mitosis, this phosphorylation promoted activation of another SAC component, benzimidazoles 1. Mutation of Bub3 Ser135 to alanine led to a defect in SAC activation. Furthermore, we found that ATM-mediated phosphorylation of Bub3 on Ser135 was also induced by ionizing radiation-induced DNA damage. However, this event resulted in independent signaling involving interaction with the Ku70–Ku80–DNA-PKcs sensor/kinase complex, leading to efficient nonhomologous end-joining repair. Taken together, we highlight the functional significance of the crosstalk between the kinetochore-oriented signal and double-strand break repair pathways via ATM phosphorylation of Bub3 on Ser135.
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