Ultraviolet Radiation and the Slug Transcription Factor Induce Proinflammatory and Immunomodulatory Mediator Expression in Melanocytes

Despite extensive investigation, the precise contribution of the ultraviolet radiation (UVR) component of sunlight to melanoma etiology remains unclear. UVR induces keratinocytes to secrete proinflammatory and immunomodulatory mediators that promote inflammation and skin tumor development; expression of the slug transcription factor in keratinocytes is required for maximal production of these mediators. In the present studies we examined the possibility that UVR-exposed melanocytes also produce proinflammatory mediators and that Slug is important in this process. Microarray studies revealed that both UVR exposure and Slug overexpression altered transcription of a variety of proinflammatory mediators by normal human melanocytes; some of these mediators are also known to stimulate melanocyte growth and migration. There was little overlap in the spectra of cytokines produced by the two stimuli. However IL-20 was similarly induced by both stimuli and the NFκB pathway appeared to be important in both circumstances. Further exploration of UVR-induced and Slug-dependent pathways of cytokine induction in melanocytes may reveal novel targets for melanoma therapy

The Framing of Urban Sustainability Transformations

Transformational change is not always intentional. However, deliberate transformations are imperative to achieve the sustainable visions that future generations deserve. Small, unintentional tweaks will not be enough to overcome persistent and emergent urban challenges. Recent scholarship on sustainability transformations has evolved considerably, but there is no consensus on what qualifies transformational change. We describe variations in current discussions of intentional sustainability transformations in the literature and synthesize strategies from funding institutions’ recent requests for proposals for urban sustainability transformations. Research funding initiatives calling for transformational change are increasingly common and are an important driver of how transformational change is articulated in research-practice in cities. From this synthesis, we present seven criteria for transformational change that provide direction for framing and implementing transformational change initiatives

Parent-child communication in sport: Bridging the gap between theory and research

Parent-child communication is integral to the acquisition of positive developmental outcomes from sport. This position paper offers useful interdisciplinary frameworks and theories for future researchers as they investigate questions pertaining to parentchild communication in organized youth sport. We propose such work is enhanced when grounded in family, human development, and interpersonal communication theory and literature. Specifically, theoretical frameworks from these areas assist researchers in determining salient research questions, choosing appropriate methodologies, and most importantly in the interpretation of findings. As researchers attempt to further understand parental influence in sport, the role of specific family processes like communication will shed light on the potential mechanisms that drive youth’s developmental outcomes. This knowledge will likely lead to better outcomes for youth participating in sport, and better relationships among family members in and out of the sport context. By gaining greater understanding of this phenomenon, researchers will have a more complete set of tools to educate parents, administrators, and coaches in an evidence-based way

Innate immune functions of microglia isolated from human glioma patients

BACKGROUND: Innate immunity is considered the first line of host defense and microglia presumably play a critical role in mediating potent innate immune responses to traumatic and infectious challenges in the human brain. Fundamental impairments of the adaptive immune system in glioma patients have been investigated; however, it is unknown whether microglia are capable of innate immunity and subsequent adaptive anti-tumor immune responses within the immunosuppressive tumor micro-environment of human glioma patients. We therefore undertook a novel characterization of the innate immune phenotype and function of freshly isolated human glioma-infiltrating microglia (GIM). METHODS: GIM were isolated by sequential Percoll purification from patient tumors immediately after surgical resection. Flow cytometry, phagocytosis and tumor cytotoxicity assays were used to analyze the phenotype and function of these cells. RESULTS: GIM expressed significant levels of Toll-like receptors (TLRs), however they do not secrete any of the cytokines (IL-1β, IL-6, TNF-α) critical in developing effective innate immune responses. Similar to innate macrophage functions, GIM can mediate phagocytosis and non-MHC restricted cytotoxicity. However, they were statistically less able to mediate tumor cytotoxicity compared to microglia isolated from normal brain. In addition, the expression of Fas ligand (FasL) was low to absent, indicating that apoptosis of the incoming lymphocyte population may not be a predominant mode of immunosuppression by microglia. CONCLUSION: We show for the first time that despite the immunosuppressive environment of human gliomas, GIM are capable of innate immune responses such as phagocytosis, cytotoxicity and TLR expression but yet are not competent in secreting key cytokines. Further understanding of these innate immune functions could play a critical role in understanding and developing effective immunotherapies to malignant human gliomas

Integrating existing climate adaptation planning into future visions: A strategic scenario for the central Arizona–Phoenix region

Cities face a number of challenges to ensure that people’s well-being and ecosystem integrity are not only maintained but improved for current and future generations. Urban planning must account for the diverse and changing interactions among the social, ecological, and technological systems (SETS) of a city. Cities struggle with long-range approaches to explore, anticipate, and plan for sustainability and resilience—and scenario development is one way to address this need. In this paper, we present the framework for developing what we call ‘strategic’ scenarios, which are scenarios or future visions created from governance documents expressing unrealized municipal priorities and goals. While scenario approaches vary based on diverse planning and decision-making objectives, only some offer tangible, systemic representations of existing plans and goals for the future that can be explored as an assessment and planning tool for sustainability and resilience. Indeed, the strategic scenarios approach presented here (1) emphasizes multi-sectoral and interdisciplinary interventions; (2) identifies systemic conflicts, tradeoffs, and synergies among existing planning goals; and (3) incorporates as yet unrealized goals and strategies representative of urban short-term planning initiatives. We present an example strategic scenario for the Central Arizona–Phoenix metropolitan region, and discuss the utility of the strategic scenario in long-term thinking for future sustainability and resilience in urban research and practice. This approach brings together diverse—sometimes competing—strategies and offers the opportunity to explore outcomes by comparing and contrasting their implications and tradeoffs, and evaluating the resulting strategic scenario against scenarios developed through alternative, participatory approaches

Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma

Immunotherapy approaches for pancreatic ductal adenocarcinoma (PDAC) have met with limited success. It has been postulated that a low mutation load may lead to a paucity of T cells within the tumor microenvironment (TME). However, it is also possible that while neoantigens are present, an effective immune response cannot be generated due to an immune suppressive TME. To discern whether targetable neoantigens exist in PDAC, we performed a comprehensive study using genomic profiles of 221 PDAC cases extracted from public databases. Our findings reveal that: (a) nearly all PDAC samples harbor potentially targetable neoantigens; (b) T cells are present but generally show a reduced activation signature; and (c) markers of efficient antigen presentation are associated with a reduced signature of markers characterizing cytotoxic T cells. These findings suggest that despite the presence of tumor specific neoepitopes, T cell activation is actively suppressed in PDAC. Further, we identify iNOS as a potential mediator of immune suppression that might be actionable using pharmacological avenues

Setting the Stage for Co-Production

Participatory scenario visioning aims to expose, integrate, and reconcile perspectives and expectations about a sustainable, resilient future from a variety of actors and stakeholders. This chapter considers the settings in which transdisciplinary participatory visioning takes place, highlighting lessons learned from the Urban Resilience to Extremes Sustainability Research Network (UREx SRN). It reflects on the benefits of engaging in the co-production process and the challenges that must be considered amid this process

Type I Interferon Regulates the Expression of Long Non-Coding RNAs

Interferons (IFNs) are key players in the antiviral response. IFN sensing by the cell activates transcription of IFN-stimulated genes (ISGs) able to induce an antiviral state by affecting viral replication and release. IFN also induces the expression of ISGs that function as negative regulators to limit the strength and duration of IFN response. The ISGs identified so far belong to coding genes. However, only a small proportion of the transcriptome corresponds to coding transcripts and it has been estimated that there could be as many coding as long noncoding RNAs (lncRNAs). To address whether IFN can also regulate the expression of lncRNAs, we analyzed the transcriptome of HuH7 cells treated or not with IFNα2 by expression arrays. Analysis of the arrays showed increased levels of several well-characterized coding genes that respond to IFN both at early or late times. Furthermore, we identified several IFN-stimulated or -downregulated lncRNAs (ISRs and IDRs). Further validation showed that ISR2, 8 and 12 expression mimics that of their neighboring genes GBP1, IRF1 and IL6, respectively, all related to the IFN response. These genes are induced in response to different doses of IFNα2 in different cell lines at early (ISR2 or 8) or later (ISR12) time points. IFNβ also induced the expression of these lncRNAs. ISR2 and 8 were also induced by an influenza virus unable to block the IFN response but not by other wild-type lytic viruses tested. Surprisingly, both ISR2 and 8 were significantly upregulated in cultured cells and livers from patients infected with HCV. Increased levels of ISR2 were also detected in patients chronically infected with HIV. This is relevant as genome-wide guilt-by-association studies predict that ISR2, 8 and 12 may function in viral processes, in the IFN pathway and the antiviral response. Therefore, we propose that these lncRNAs could be induced by IFN to function as positive or negative regulators of the antiviral response