"Re-educating" tumor-associated macrophages by targeting NF-kappaB

The nuclear factor kappaB (NF-kappaB) signaling pathway is important in cancer-related inflammation and malignant progression. Here, we describe a new role for NF-kappaB in cancer in maintaining the immunosuppressive phenotype of tumor-associated macrophages (TAMs). We show that macrophages are polarized via interleukin (IL)-1R and MyD88 to an immunosuppressive "alternative" phenotype that requires IkappaB kinase beta-mediated NF-kappaB activation. When NF-kappaB signaling is inhibited specifically in TAMs, they become cytotoxic to tumor cells and switch to a "classically" activated phenotype; IL-12(high), major histocompatibility complex II(high), but IL-10(low) and arginase-1(low). Targeting NF-kappaB signaling in TAMs also promotes regression of advanced tumors in vivo by induction of macrophage tumoricidal activity and activation of antitumor activity through IL-12-dependent NK cell recruitment. We provide a rationale for manipulating the phenotype of the abundant macrophage population already located within the tumor microenvironment; the potential to "re-educate" the tumor-promoting macrophage population may prove an effective and novel therapeutic approach for cancer that complements existing therapies

Disturbance, dispersal and marine assemblage structure: A case study from the nearshore Southern Ocean

Disturbance is a key factor in most natural environments and, globally, disturbance regimes are changing, driven by increased anthropogenic influences, including climate change. There is, however, still a lack of understanding about how disturbance interacts with species dispersal capacity to shape marine assemblage structure. We examined the impact of ice scour disturbance history (2009–2016) on the nearshore seafloor in a highly disturbed region of the Western Antarctic Peninsula by contrasting the response of two groups with different dispersal capacities: one consisting of high-dispersal species (mobile with pelagic larvae) and one of low-dispersal species (sessile with benthic larvae). Piecewise Structural Equation Models were constructed to test multi-factorial predictions of the underlying mechanisms, based on hypothesised responses to disturbance for the two groups. At least two or three disturbance factors, acting at different spatial scales, drove assemblage composition. A comparison between both high- and low-dispersal models demonstrated that these mechanisms are dispersal dependent. Disturbance should not be treated as a single metric, but should incorporate remote and direct disturbance events with consideration of taxa-dispersal and disturbance legacy. These modelling approaches can provide insights into how disturbance shapes assemblages in other disturbance regimes, such as fire-prone forests and trawl fisheries

Extremal limit of the regular charged black holes in nonlinear electrodynamics

The near horizon limit of the extreme nonlinear black hole is investigated. It is shown that resulting geometry belongs to the AdS2xS2 class with different modules of curvatures of subspaces and could be described in terms of the Lambert functions. It is demonstrated that the considered class of Lagrangians does not admit solutions of the Bertotti-Robinson type

Maria gordon buse, MD: A family affair through six decades of diabetes discovery

Maria Gordon Buse, MD, is a product of wartime Europe. She completed her professional education in four languages on three continents and continues a nearly 60-year career as an investigator, educator, and practicing endocrinologist. This brief reprisal is written collabora-tively by her biological offspring and in-tellectual progeny, an appropriate reflection of a career where family and work were joyfully intertwined in an irresolvable way

Cigarette Smoking, Birthweight and Osteoporosis in Adulthood: Results from the Hertfordshire Cohort Study

We looked for interaction between early environment and adult lifestyle in determination of bone mineral content (BMC) and bone mineral density (BMD) among 498 men and 468 women for whom birth records were available. Participants completed a health questionnaire, and bone densitometry (DXA) of the lumbar spine and femoral neck performed

The landscape of gifted and talented education in England and Wales: How are teachers implementing policy?

This is an Author's Accepted Manuscript of an article published in Research Papers in Education, 27(2), 167-186, 2012, copyright Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/02671522.2010.509514.This paper explores the evidence relating to how primary schools are responding to the ‘gifted and talented’ initiative in England and Wales. A questionnaire survey which invited both closed and open-ended responses was carried out with a national sample of primary schools. The survey indicated an increasing proportion of coordinators, compared with a survey carried out in 1996, were identifying their gifted and talented children as well as having associated school policies. However, the survey also highlighted a number of issues which need addressing if the initiative is to achieve its objective of providing the best possible educational opportunities for children. For example, it was found that a significant number of practitioners were not aware of the existence of the National Quality Standards for gifted and talented education, provided by the UK government in 2007, and the subject-specific criteria provided by the UK’s Curriculum Authority for identification and provision have been largely ignored. The process of identifying children to be placed on the ‘gifted and talented’ register seems haphazard and based on pragmatic reasons. Analysis of teachers’ responses also revealed a range of views and theoretical positioning held by them, which have implications for classroom practice. As the ‘gifted and talented’ initiative in the UK is entering a second decade, and yet more significant changes in policy are introduced, pertinent questions need to be raised and given consideration

Cold Plasma Dispersion Relations in the Vicinity of a Schwarzschild Black Hole Horizon

We apply the ADM 3+1 formalism to derive the general relativistic magnetohydrodynamic equations for cold plasma in spatially flat Schwarzschild metric. Respective perturbed equations are linearized for non-magnetized and magnetized plasmas both in non-rotating and rotating backgrounds. These are then Fourier analyzed and the corresponding dispersion relations are obtained. These relations are discussed for the existence of waves with positive angular frequency in the region near the horizon. Our results support the fact that no information can be extracted from the Schwarzschild black hole. It is concluded that negative phase velocity propagates in the rotating background whether the black hole is rotating or non-rotating.Comment: 27 pages, 11 figures accepted for publication in Gen. Relat. & Gravi

The extremes of disturbance reduce functional redundancy: Functional trait assessment of the shallow Antarctic benthos

Climate-driven changes in disturbance are a major threat to ecosystem Functional diversity. The selective mechanisms underlying ecosystem response to disturbance are far from universal and remain the subject of scientific debate. Ice scouring of the shallow Antarctic benthos is one of the largest disturbance gradients in the natural environment and thus provides an opportunity to investigate how disturbance gradients influence functional structure of a biological assemblage. The Western Antarctic Peninsula, in particular, is a hotspot of climate-driven environmental change. Addressing how this system might respond to species loss is critical. Previous surveys across the shallowest 100 m of the seabed, detected unimodal changes in diversity and a shift in assemblage composition in response to disturbance gradients. This study investigated how functional traits and associated functional diversity change across the depth gradient. Our results revealed that selective mechanisms, such as disturbance filtering and inter-species competition, reduce functional redundancy at the extremes of the disturbance gradient. Our study highlights areas of potential vulnerability to future environmental change due to low functional redundancy. Threatening the important negative (mitigating) feedbacks on climate change, through blue carbon, currently provided by Antarctic continental shelf benthic assemblages

Optimising approximate entropy for assessing cardiac dyssynchrony with radionuclide ventriculography

Left ventricular dyssynchrony can be assessed with phase parameters from radionuclide ventriculography (RNVG), including approximate entropy (ApEn). The input values used to calculate ApEn will affect the results significantly, so it is essential to optimise ApEn for the application. However to date, no optimisation for ApEn applied to images has been published. In this paper, generated data were used to simulate patient phase images, allowing the input parameters for ApEn to be tested and optimised in a controlled environment. Clinical images were then used to confirm that the selected parameters were appropriate. The results demonstrate the effect of input parameters for ApEn and the most appropriate use with RNVG phase images. This work demonstrates the importance of optimisation and standardisation when using ApEn as a measure of dyssynchrony

The SUMO protease SENP3 regulates mitochondrial autophagy mediated by Fis1

Mitochondria are unavoidably subject to organellar stress resulting from exposure to a range of reactive molecular species. Consequently, cells operate a poorly understood quality control programme of mitophagy to facilitate elimination of dysfunctional mitochondria. Here, we used a model stressor, deferiprone (DFP), to investigate the molecular basis for stress-induced mitophagy. We show that mitochondrial fission 1 protein (Fis1) is required for DFP-induced mitophagy and that Fis1 is SUMOylated at K149, an amino acid residue critical for Fis1 mitochondrial localization. We find that DFP treatment leads to the stabilization of the SUMO protease SENP3, which is mediated by downregulation of the E3 ubiquitin (Ub) ligase CHIP. SENP3 is responsible for Fis1 deSUMOylation and depletion of SENP3 abolishes DFP-induced mitophagy. Furthermore, preventing Fis1 SUMOylation by conservative K149R mutation enhances Fis1 mitochondrial localization. Critically, expressing a Fis1 K149R mutant restores DFP-induced mitophagy in SENP3-depleted cells. Thus, we propose a model in which SENP3-mediated deSUMOylation facilitates Fis1 mitochondrial localization to underpin stress-induced mitophagy