Liftings, Young measures, and lower semicontinuity

This work introduces liftings and their associated Young measures as new tools to study the asymptotic behaviour of sequences of pairs $(u_j,Du_j)j$ for $(u_j)_j \in \mathrm{BV}(\Omega;\mathbb{R}^m)$ under weak* convergence. These tools are then used to prove an integral representation theorem for the relaxation of the functional $$\mathcal{F}\colon u\to\int_\Omega f(x,u(x),\nabla u(x)) \;\mathrm{dx},\quad u\in\mathrm{W}^{1,1}({\Omega};\mathbb{R}^m),\quad {\Omega}\in\mathbb{R}^d\text{ open},$$ to the space $\mathrm{BV}(\Omega; \mathbb{R}^m)$. Lower semicontinuity results of this type were first obtained by Fonseca and M\"uller [Arch. Ration. Mech. Anal. 123 (1993), 1-49] and later improved by a number of authors, but our theorem is valid under more natural, essentially optimal, hypotheses than those currently present in the literature, requiring principally that $f$ be Carath\'eodory and quasiconvex in the final variable. The key idea is that liftings provide the right way of localising $\mathcal{F}$ in the $x$ and $u$ variables simultaneously under weak* convergence. As a consequence, we are able to implement an optimal measure-theoretic blow-up procedure.Comment: 75 pages. Updated to correct a series of minor typos/ inaccuracies. The statement and proof of Theorem have also been amended- subsequent steps relying upon the Theorem did not require updatin

Relaxation for partially coercive integral functionals with linear growth

We prove an integral representation theorem for the $\mathrm{L}^1$-relaxation of the functional $\mathcal{F}\colon u\mapsto\int_\Omega f(x,u(x),\nabla u(x))\;\mathrm{d} x,\quad u\in\mathrm{W}^{1,1}(\Omega;\mathbb{R}^m)$, where $\Omega\subset\mathbb{R}^d$ ($d \geq 2$) is a bounded Lipschitz domain, to the space $\mathrm{BV}(\Omega;\mathbb{R}^m)$ under very general assumptions: we require principally that $f$ is Carathéodory, that the partial coercivity and linear growth bound $g(x,y)|A|\leq f(x,y,A)\leq Cg(x,y)(1+|A|)$, hold, where $g\colon\overline{\Omega}\times\mathbb{R}^m\to[0,\infty)$ is a continuous function satisfying a weak monotonicity condition, and that $f$ is quasi-convex in the final variable. Our result is the first that applies to integrands which are unbounded in the $u$-variable and, therefore, allows for the treatment of many problems from applications. Such functionals are out of reach of the classical blowup approach introduced by Fonseca and Müller [Arch. Ration. Mech. Anal., 123 (1993), pp. 1--49]. Our proof relies on an intricate truncation construction (in the $x$- and $u$-arguments simultaneously) made possible by the theory of liftings developed in a previous paper by the authors [Arch. Ration. Mech. Anal., 232 (2019), pp. 1227--1328], and features techniques which could be of use for other problems involving $u$-dependent integrands

The psychology of news influence and development of Media Framing Analysis

HowHow precisely do media influence their readers, listeners and viewers? In this paper, we argue that any serious study of the psychology of media influence must incorporate a systematic analysis of media material. However, psychology presently lacks a methodology for doing this that is sensitive to context, relying on generalised methods like content or discourse analysis. In this paper, we develop an argument to support our development of a technique that we have called Media Framing Analysis (MFA), a formal procedure for conducting analyses of (primarily news) media texts. MFA draws on elements of existing framing research from communication and other social scientific research while at the same time incorporating features of particular relevance to psychology, such as narrative and characterisation

"Crack down on the celebrity junkies": does media coverage of celebrity drug use pose a risk to young people?

This study analysed news media content to examine the role played by celebrity drug use in young people's perceptions of drug use. We know that young people have access to discourses of drug use through music and other media which may emphasise short term gains (of pleasure or sexual success) over longer term health and social problems. This study goes beyond a simple modelling approach by using Media Framing Analysis (MFA) to take an in-depth look at the messages themselves and how they are 'framed'. New stories about Amy Winehouse's drug use were used and we conducted focus groups with young people asking them questions about drugs, celebrity and the media. Frames identified include: 'troubled genius', 'losing patience' and 'glamorization or gritty realism'. Initially, the press championed Winehouse's musical talent but soon began to tire of her recklessness; the participants tended to be unimpressed with Winehouse's drug use, characterising her as a promising artist who had 'gone off the rails'. Young people were far more critical of Winehouse than might be expected, demonstrating that concerns about the influence of celebrity drug use and its impact on future health risk behaviour among young people may have been over-simplified and exaggerated. This study illustrates the need to understand young people and their frames of reference within popular culture when designing drug awareness information relevant to them. Furthermore, it indicates that critical media skills analysis may contribute to health risk education programmes related to drug use

AGI-134: a fully synthetic alpha-Gal glycolipid that converts tumors into in situ autologous vaccines, induces anti-tumor immunity and is synergistic with an anti-PD-1 antibody in mouse melanoma models

Background: Treatments that generate T cell-mediated immunity to a patient\u27s unique neoantigens are the current holy grail of cancer immunotherapy. In particular, treatments that do not require cumbersome and individualized ex vivo processing or manufacturing processes are especially sought after. Here we report that AGI-134, a glycolipid-like small molecule, can be used for coating tumor cells with the xenoantigen Galalpha1-3Galbeta1-4GlcNAc (alpha-Gal) in situ leading to opsonization with pre-existing natural anti-alpha-Gal antibodies (in short anti-Gal), which triggers immune cascades resulting in T cell mediated anti-tumor immunity. Methods: Various immunological effects of coating tumor cells with alpha-Gal via AGI-134 in vitro were measured by flow cytometry: (1) opsonization with anti-Gal and complement, (2) antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells, and (3) phagocytosis and antigen cross-presentation by antigen presenting cells (APCs). A viability kit was used to test AGI-134 mediated complement dependent cytotoxicity (CDC) in cancer cells. The anti-tumoral activity of AGI-134 alone or in combination with an anti-programmed death-1 (anti-PD-1) antibody was tested in melanoma models in anti-Gal expressing galactosyltransferase knockout (alpha1,3GT(-/-)) mice. CDC and phagocytosis data were analyzed by one-way ANOVA, ADCC results by paired t-test, distal tumor growth by Mantel-Cox test, C5a data by Mann-Whitney test, and single tumor regression by repeated measures analysis. Results: In vitro, alpha-Gal labelling of tumor cells via AGI-134 incorporation into the cell membrane leads to anti-Gal binding and complement activation. Through the effects of complement and ADCC, tumor cells are lysed and tumor antigen uptake by APCs increased. Antigen associated with lysed cells is cross-presented by CD8alpha+ dendritic cells leading to activation of antigen-specific CD8+ T cells. In B16-F10 or JB/RH melanoma models in alpha1,3GT(-/-) mice, intratumoral AGI-134 administration leads to primary tumor regression and has a robust abscopal effect, i.e., it protects from the development of distal, uninjected lesions. Combinations of AGI-134 and anti-PD-1 antibody shows a synergistic benefit in protection from secondary tumor growth. Conclusions: We have identified AGI-134 as an immunotherapeutic drug candidate, which could be an excellent combination partner for anti-PD-1 therapy, by facilitating tumor antigen processing and increasing the repertoire of tumor-specific T cells prior to anti-PD-1 treatment

Representations of voluntary childlessness in the UK Press, 1990-2008

Representations of voluntary childlessness — the declaration by an individual that he or she does not wish to bear or raise children — were studied in 116 articles published in British national newspapers in the period 1990—2008. Media framing analysis was used to examine broad patterns of framing of the topic, identifying four frames: voluntary childlessness as an individual rights issue, as a form of resistance, as a social trend, and as a personal decision. These frames, it is argued, may act as potential ‘scripts’ for newspaper readers who are debating the decision to start a family

Elraglusib (9-ING-41), a selective small-molecule inhibitor of glycogen synthase kinase-3 beta, reduces expression of immune checkpoint molecules PD-1, TIGIT and LAG-3 and enhances CD8+ T cell cytolytic killing of melanoma cells

Background Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with multiple roles in tumour growth, cell invasion and metastasis. We have previously established GSK-3 as an upstream regulator of PD-1 gene expression in CD8 + T cells and demonstrated that GSK-3 inhibition is as effective as anti-PD-1 mAb blockade in controlling tumour growth. Elraglusib (9-ING-41) is a specific small-molecule inhibitor of GSK-3β with clinical activity in patients with advanced cancers, including a patient with refractory melanoma whose response provided the rationale for the current study. Methods The B16 melanoma mouse model was used to observe the effect of elraglusib on tumour growth either as a single agent or in combination (simultaneously and sequentially) with anti-PD-1 mAb treatment. B16 tumour cells were implanted in either the flank, brain or both locations, and Kaplan–Meier plots were used to depict survival and significance determined using log rank tests. Expression of the immune checkpoint molecules, TIGIT, LAG-3 and PD-1, was evaluated using flow cytometry alongside expression of the chemokine receptor, CXCR3. Further evaluation of PD-1 expression was determined through RT-qPCR and immunohistochemistry. Results We demonstrated that elraglusib has a suppressive effect against melanoma as a single agent and enhanced anti-PD-1 therapy. There was a synergistic effect when elraglusib was used in combination with anti-PD-1 mAb, and an even greater effect when used as sequential therapy. Suppression of tumour growth was associated with a reduced expression of immune checkpoint molecules, PD-1, TIGIT and LAG-3 with upregulation of CXCR3 expression. Conclusions These data highlight the potential of elraglusib as an immune-modulatory agent and demonstrate the benefit of a sequential approach with immune checkpoint inhibition followed by GSK-3β inhibition in melanoma and provide a rationale for clinical investigation of elraglusib combined with immune checkpoint inhibitory molecules, including those targeting PD-1, TIGIT and LAG-3. This has several potential implications for current immunotherapy regimes, including possibly reducing the intensity of anti-PD-1 mAb treatment needed for response in patients receiving elraglusib, especially given the benign adverse event profile of elraglusib observed to date. Based on these data, a clinical study of elraglusib, an anti-PD-1 mAb and chemotherapy is ongoing (NCT NCT05239182)

Molecular detection of Toxoplasma gondii in water samples from Scotland and a comparison between the 529bp real-time PCR and ITS1 nested PCR

Waterborne transmission of Toxoplasma gondii is a potential public health risk and there are currently no agreed optimised methods for the recovery, processing and detection of T. gondii oocysts in water samples. In this study modified methods of T. gondii oocyst recovery and DNA extraction were applied to 1427 samples collected from 147 public water supplies throughout Scotland. T. gondii DNA was detected, using real time PCR (qPCR) targeting the 529bp repeat element, in 8.79% of interpretable samples (124 out of 1411 samples). The samples which were positive for T. gondii DNA originated from a third of the sampled water sources. The samples which were positive by qPCR and some of the negative samples were reanalysed using ITS1 nested PCR (nPCR) and results compared. The 529bp qPCR was the more sensitive technique and a full analysis of assay performance, by Bayesian analysis using a Markov Chain Monte Carlo method, was completed which demonstrated the efficacy of this method for the detection of T. gondii in water samples