Digital afx: digital dressing and affective shifts in Sin City and 300

In Sin City (Robert Rodriguez, 2005) and 300 (Zack Snyder, 2006) extensive post-production work has created stylised colour palettes, manipulated areas of the image, and added or subtracted elements. Framing a discussion around the terms ‘affect’ and ‘emotion’, this paper argues that the digital technologies used in Sin City and 300 modify conventional interactions between representational and aesthetic dimensions. Brian Massumi suggests affective imagery can operate through two modes of engagement. One mode is embedded in a meaning system, linked to a speci?c emotion. The second is understood as an intensi?cation whereby a viewer reacts but that reaction is not yet gathered into an alignment with meaning. The term ‘digital afx’ is used to describe manipulations that produce imagery allowing these two modes of engagement to coexist. Digital afx are present when two competing aesthetic strategies remain equally visible within sequences of images. As a consequence the afx mingle with and shift the content of representation

TAM family receptors in conjunction with MAPK signalling are involved in acquired resistance to PI3Kα inhibition in head and neck squamous cell carcinoma.

BACKGROUND: Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway is common in many malignancies, including head and neck squamous cell carcinoma (HNSCC). Despite pre-clinical and clinical studies, outcomes from targeting the PI3K pathway have been underwhelming and the development of drug resistance poses a significant barrier to patient treatment. In the present study, we examined mechanisms of acquired resistance to the PI3Kα inhibitor alpelisib (formerly BYL719) in HNSCC cell lines and patient-derived xenografts (PDXs). METHODS: Five unique PDX mouse models and three HNSCC cell lines were used. All cell lines and xenografts underwent genomic characterization prior to study. Serial drug treatment was conducted in vitro and in vivo to develop multiple, clinically-significant models of resistance to alpelisib. We then used reverse phase protein arrays (RPPAs) to profile the expression of proteins in parental and drug-resistant models. Top hits were validated by immunoblotting and immunohistochemistry. Flow cytometric analysis and RNA interference studies were then used to interrogate the molecular mechanisms underlying acquired drug resistance. RESULTS: Prolonged treatment with alpelisib led to upregulation of TAM family receptor tyrosine kinases TYRO3 and AXL. Importantly, a significant shift in expression of both TYRO3 and AXL to the cell surface was detected in drug-resistant cells. Targeted knockdown of TYRO3 and AXL effectively re-sensitized resistant cells to PI3Kα inhibition. In vivo, resistance to alpelisib emerged following 20-35 days of treatment in all five PDX models. Elevated TYRO3 expression was detected in drug-resistant PDX tissues. Downstream of TYRO3 and AXL, we identified activation of intracellular MAPK signalling. Inhibition of MAPK signalling also re-sensitized drug-resistant cells to alpelisib. CONCLUSIONS: We have identified TYRO3 and AXL receptors to be key mediators of resistance to alpelisib, both in vitro and in vivo. Our findings suggest that pan-TAM inhibition is a promising avenue for combinatorial or second-line therapy alongside PI3Kα inhibition. These findings advance our understanding of the role TAM receptors play in modulating the response of HNSCC to PI3Kα inhibition and suggest a means to prevent, or at least delay, resistance to PI3Kα inhibition in order to improve outcomes for HNSCC patients

Mutational analysis of head and neck squamous cell carcinoma stratified by smoking status.

Smoking has historically been recognized as a negative prognostic factor in head and neck squamous cell carcinoma (HNSCC). This study aimed to assess the mutational differences between heavy smokers (\u3e20 pack years) and never smokers among the HNSCC patients within The Cancer Genome Atlas (TCGA). Single nucleotide variation and copy number aberration differences between heavy smokers and never smokers were compared within human papillomavirus-positive (HPV-positive) (n = 67) and HPV-negative (n = 431) TCGA cohorts with HNSCC, and the impact of these mutations on survival were assessed. No genes were differentially mutated between smoking and never-smoking patients with HPV-positive tumors. By contrast, in HPV-negative tumors, NSD1 and COL1A11 were found to be more frequently mutated in heavy smokers, while CASP8 was more frequently altered in never smokers. HPV-negative patients with NSD1 mutations experienced significantly improved overall survival compared with NSD1 WT patients. This improved prognosis was validated in an independent cohort of 77 oral cavity cancer patients and a meta-analysis that included 2 additional data sets (688 total patients, hazard ratio for death 0.44, 95% CI, 0.30-0.65). NSD1 mutations are more common in HPV-negative heavy smokers, define a cohort with favorable prognosis, and may represent a clinically useful biomarker to guide treatment deintensification for HPV-negative patients

Research Needs and Challenges in the FEW System: Coupling Economic Models with Agronomic, Hydrologic, and Bioenergy Models for Sustainable Food, Energy, and Water Systems

On October 12–13, a workshop funded by the National Science Foundation was held at Iowa State University in Ames, Iowa with a goal of identifying research needs related to coupled economic and biophysical models within the FEW system. Approximately 80 people attended the workshop with about half representing the social sciences (primarily economics) and the rest from the physical and natural sciences. The focus and attendees were chosen so that findings would be particularly relevant to SBE research needs while taking into account the critical connectivity needed between social sciences and other disciplines. We have identified several major gaps in existing scientific knowledge that present substantial impediments to understanding the FEW system. We especially recommend research in these areas as a priority for future funding: 1. Economic models of decision-making in coupled systems Deliberate human activity has been the dominant factor driving environmental and land-use changes for hundreds of years. While economists have made great strides in modeling and understanding these choices, the coupled systems modeling literature, with some important exceptions, has not reflected these contributions. Several paths forward seem fruitful. First, baseline economic models that assume rationality can be used much more widely than they are currently. Moreover, the current generation of IAMs that include rational agents have emphasized partial equilibrium studies appropriate for smaller systems. To allow this approach to be used to study larger systems, the potential for (and consequences of) general equilibrium effects should be studied as well. Second, it is important to address shortcomings in these models of economic decision-making. Valuable improvements could be gained from developing coupled models that draw insights from behavioral economics. Many decision-makers deviate systematically from actions that would be predicted by strict rationality, but very few IAMs incorporate this behavior, potentially leading to inaccurate predictions about the effects of policies and regulations. Improved models of human adaptation and induced technological change can also be incorporated into coupled models. Particularly for medium to long-run models, decisions about adaptation and technological change will have substantial effects on the conclusions and policy implications, but more compelling methods for incorporating these changes into modeling are sorely needed. In addition, some economic decisions are intrinsically dynamic yet few coupled models explicitly incorporate dynamic models. Economic models that address uncertainty in decision making are also underutilized in coupled models of the FEW system. 2. Coupling models across disciplines Despite much recent progress, established models for one component of the FEW system often cannot currently produce outcomes that can be used as inputs for models of other components. This misalignment makes integrated modeling difficult and is especially apparent in linking models of natural phenomena with models of economic decision-making. Economic agents typically act to maximize a form of utility or welfare that is not directly linked to physical processes, and they typically require probabilistic forecasts as an input to their decision-making that many models in the natural sciences cannot directly produce. We believe that an especially promising approach is the development of “bridge” models that convert outputs from one model into inputs for another. Such models can be viewed as application-specific, reduced-form distillations of a richer and more realistic underlying model. Ideally, these bridge models would be developed in collaborative research projects involving economists, statisticians, and disciplinary specialists, and would contribute to improved understanding in the scientific discipline as well. 3. Model validation and comparison There is little clarity on how models should be evaluated and compared to each other, both within individual disciplines and as components of larger IAMs. This challenge makes larger integrated modeling exercises extremely difficult. Some potential ways to advance are by developing statistical criteria that measure model performance along the dimensions suitable for inclusion in an IAM as well as infrastructure and procedures to facilitate model comparisons. Focusing on the models’ out-of-sample distributional forecasting performance, as well as that of the IAM overall, is especially promising and of particular importance. Moreover, applications of IAMs tend to estimate the effect of hypothetical future policy actions, but there have been very few studies that have used these models to estimate the effect of past policy actions. These exercises should be encouraged. They offer a well-understood test bed for the IAMs, and also contribute to fundamental scientific knowledge through better understanding of the episode in question. The retrospective nature of this form of analysis also presents the opportunity to combine reduced-form estimation strategies with the IAMs as an additional method of validation

Inflammatory dendritic cells—not basophils—are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen

It is unclear how Th2 immunity is induced in response to allergens like house dust mite (HDM). Here, we show that HDM inhalation leads to the TLR4/MyD88-dependent recruitment of IL-4 competent basophils and eosinophils, and of inflammatory DCs to the draining mediastinal nodes. Depletion of basophils only partially reduced Th2 immunity, and depletion of eosinophils had no effect on the Th2 response. Basophils did not take up inhaled antigen, present it to T cells, or express antigen presentation machinery, whereas a population of FceRI+ DCs readily did. Inflammatory DCs were necessary and sufficient for induction of Th2 immunity and features of asthma, whereas basophils were not required. We favor a model whereby DCs initiate and basophils amplify Th2 immunity to HDM allergen

Genome-wide Association Study of Platelet Count Identifies Ancestry-Specific Loci in Hispanic/Latino Americans

Platelets play an essential role in hemostasis and thrombosis. We performed a genome-wide association study of platelet count in 12,491 participants of the Hispanic Community Health Study/Study of Latinos by using a mixed-model method that accounts for admixture and family relationships. We discovered and replicated associations with five genes (ACTN1, ETV7, GABBR1-MOG, MEF2C, and ZBTB9-BAK1). Our strongest association was with Amerindian-specific variant rs117672662 (p value = 1.16 × 10−28) in ACTN1, a gene implicated in congenital macrothrombocytopenia. rs117672662 exhibited allelic differences in transcriptional activity and protein binding in hematopoietic cells. Our results underscore the value of diverse populations to extend insights into the allelic architecture of complex traits

Human dermal CD14⁺ cells are a transient population of monocyte-derived macrophages.

Dendritic cells (DCs), monocytes, and macrophages are leukocytes with critical roles in immunity and tolerance. The DC network is evolutionarily conserved; the homologs of human tissue CD141(hi)XCR1⁺ CLEC9A⁺ DCs and CD1c⁺ DCs are murine CD103⁺ DCs and CD64⁻ CD11b⁺ DCs. In addition, human tissues also contain CD14⁺ cells, currently designated as DCs, with an as-yet unknown murine counterpart. Here we have demonstrated that human dermal CD14⁺ cells are a tissue-resident population of monocyte-derived macrophages with a short half-life of <6 days. The decline and reconstitution kinetics of human blood CD14⁺ monocytes and dermal CD14⁺ cells in vivo supported their precursor-progeny relationship. The murine homologs of human dermal CD14⁺ cells are CD11b⁺ CD64⁺ monocyte-derived macrophages. Human and mouse monocytes and macrophages were defined by highly conserved gene transcripts, which were distinct from DCs. The demonstration of monocyte-derived macrophages in the steady state in human tissue supports a conserved organization of human and mouse mononuclear phagocyte system

The mucosal immune system and its regulation by autophagy

The gastrointestinal tract presents a unique challenge to the mucosal immune system, which has to constantly monitor the vast surface for the presence of pathogens, while at the same time maintaining tolerance to beneficial or innocuous antigens. In the intestinal mucosa, specialized innate and adaptive immune components participate in directing appropriate immune responses toward these diverse challenges. Recent studies provide compelling evidence that the process of autophagy influences several aspects of mucosal immune responses. Initially described as a “self-eating” survival pathway that enables nutrient recycling during starvation, autophagy has now been connected to multiple cellular responses, including several aspects of immunity. Initial links between autophagy and host immunity came from the observations that autophagy can target intracellular bacteria for degradation. However, subsequent studies indicated that autophagy plays a much broader role in immune responses, as it can impact antigen processing, thymic selection, lymphocyte homeostasis, and the regulation of immunoglobulin and cytokine secretion. In this review, we provide a comprehensive overview of mucosal immune cells and discuss how autophagy influences many aspects of their physiology and function. We focus on cell type-specific roles of autophagy in the gut, with a particular emphasis on the effects of autophagy on the intestinal T cell compartment. We also provide a perspective on how manipulation of autophagy may potentially be used to treat mucosal inflammatory disorders