Interferon-γ links ultraviolet radiation to melanomagenesis in mice

Cutaneous malignant melanoma is a highly aggressive and frequently chemoresistant cancer, the incidence of which continues to rise. Epidemiological studies show that the major aetiological melanoma risk factor is ultraviolet (UV) solar radiation, with the highest risk associated with intermittent burning doses, especially during childhood. We have experimentally validated these epidemiological findings using the hepatocyte growth factor/scatter factor transgenic mouse model, which develops lesions in stages highly reminiscent of human melanoma with respect to biological, genetic and aetiological criteria, but only when irradiated as neonatal pups with UVB, not UVA. However, the mechanisms underlying UVB-initiated, neonatal-specific melanomagenesis remain largely unknown. Here we introduce a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. We use expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon response signature, including genes associated with immunoevasion. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody-mediated systemic blockade of interferon-γ (IFN-γ), but not type-I interferons. IFN-γ was produced by macrophages recruited to neonatal skin by UVB-induced ligands to the chemokine receptor Ccr2. Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-γ blockade abolished macrophage-enhanced melanoma growth and survival. IFN-γ-producing macrophages were also identified in 70% of human melanomas examined. Our data reveal an unanticipated role for IFN-γ in promoting melanocytic cell survival/immunoevasion, identifying a novel candidate therapeutic target for a subset of melanoma patients.     

传递矩阵方法与矩形势垒的量子隧穿

利用传递矩阵方法精确计算了一维定态薛定谔方程,求解出电子穿过矩形势垒的透射系数,进一步研究了该透射系数与有效质量和矩形势垒参数的关系。数值计算结果表明,有效质量和矩形势垒参数对透射系数的影响同等重要。     

钱家营矿选煤厂重选方案优化

在对钱家营矿原煤特性分析的基础上,利用选煤优化软件进行计算机优化,得出钱家营矿选煤厂重力分选最佳方案:各层煤单独分选出不同的精煤产品或采用选后配煤的方法将单独分选出的产品混合,以获得用户要求的产品.该方案比混合分选或混合后分级入选精煤产率高,可为选煤厂带来更好的经济效益.     

城市市政基础设施投资与经济发展的空间交互影响

通过空间联立方程模型,基于2011和2016年241个城市样本数据,研究城市市政基础设施投资与经济发展的双向互馈及其空间相互作用.结果表明:1)考虑内生性后,基础设施投资的空间滞后项系数显著为正,地方政府在投资行为上模仿彼此;2)基础设施投资与经济发展之间存在双向互促作用.建议加强对基础设施投资的预算管理,改革晋升绩效...     

The PDZ2 domain of zonula occludens-1 and -2 is a phosphoinositide binding domain

Zonula occludens proteins (ZO) are postsynaptic density protein-95 discs large-zonula occludens (PDZ) domain-containing proteins that play a fundamental role in the assembly of tight junctions and establishment of cell polarity. Here, we show that the second PDZ domain of ZO-1 and ZO-2 binds phosphoinositides (PtdInsP) and we identified critical residues involved in the interaction. Furthermore, peptide and PtdInsP binding of ZO PDZ2 domains are mutually exclusive. Although lipid binding does not seem to be required for plasma membrane localisation of ZO-1, phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P ₂) binding to the PDZ2 domain of ZO-2 regulates ZO-2 recruitment to nuclear speckles. Knockdown of ZO-2 expression disrupts speckle morphology, indicating that ZO-2 might play an active role in formation and stabilisation of these subnuclear structures. This study shows for the first time that ZO isoforms bind PtdInsPs and offers an alternative regulatory mechanism for the formation and stabilisation of protein complexes in the nucleus.     

The Documentary Real: Thinking Documentary Aesthetics

In this article we consider the growing interest in recent years in the use of documentary strategies in the wold of contemporary art, film and performing arts and explore some of the central epistemological assumptions underpinning the persistent idea that the documentary should be equated with ‘non-fiction’. Following Stella Bruzzi we argue that if documentary theory maintains objectivity as the primary measure of value, it will inevitably and continuously arrive at the conclusion that the documentary genre is fundamentally flawed. Instead, we propose to move beyond the ‘realist epistemology’ of documentary theory and focus on the ‘documentary real’, i.e. the specific performativity of the reality constructed in and by the documentary genre. In the last paragraphs, we introduce the various articles that address the “documentary real” in this special issue.     

Helmholtz's Kant revisited (Once more). The all-pervasive nature of Helmholtz's struggle with Kant's Anschauung

In this analysis, the classical problem of Hermann von Helmholtz's (1821–1894) Kantianism is explored from a particular vantage point, that to my knowledge, has not received the attention it deserves notwithstanding its possible key role in disentangling Helmholtz's relation to Kant's critical project. More particularly, we will focus on Helmholtz's critical engagement with Kant's concept of intuition [Anschauung] and (the related issue of) his dissatisfaction with Kant's doctrinal dualism. In doing so, it soon becomes clear that both (i) crucially mediated Helmholtz's idiosyncratic appropriation and criticism of (certain aspects of) Kant's critical project, and (ii) can be considered as a common denominator in a variety of issues that are usually addressed separately under the general header of (the problem of) Helmholtz's Kantianism. The perspective offered in this analysis can not only shed interesting new light on some interpretive issues that have become commonplace in discussions on Helmholtz's Kantianism, but also offers a particular way of connecting seemingly unrelated dimensions of Helmholtz's engagement with Kant's critical project (e.g. Helmholtz's views on causality and space). Furthermore, it amounts to the rather surprising conclusion that Helmholtz's most drastic revision of Kant's project pertains to his assumption of free will as a formal condition of experience and knowledge.     

Evidence for the intracellular accumulation of anandamide in adiposomes

Anandamide is a lipid messenger that carries out a wide variety of biological functions. It has been suggested that anandamide accumulation involves binding to a saturable cellular component. To identify the structure(s) involved in this process, we analyzed the intracellular distribution of both biotinylated and radiolabeled anandamide, providing direct evidence that lipid droplets, also known as adiposomes, constitute a dynamic reservoir for the sequestration of anandamide. In addition, confocal microscopy and biochemical studies revealed that the anandamide-hydrolase is also spatially associated with lipid droplets, and that cells with a larger adiposome compartment have an enhanced catabolism of anandamide. Overall, these findings suggest that adiposomes may have a critical role in accumulating anandamide, possibly by connecting plasma membrane to internal organelles along the metabolic route of this endocannabinoid. S. Oddi, F. Fezza: These authors contributed equally to the study.     

Common variants near MC4R are associated with fat mass, weight and risk of obesity

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.