"Gamma Ray" is a song by American rock musician Beck. It was released as the second single from his eighth studio album, Modern Guilt, on August 11, 2008.[1] It is seemingly inspired by the surf rock songs of the 1960s, but with ghostly moans and lyrics on the state of the world. The title refers to gamma rays, biologically hazardous energy emitted by radioactive decay. Despite its up-tempo beat, the song lyrics invoke nihilistic or apocalyptic themes, including melting ice caps, boredom, burning houses, crowns of thorns, and natural disasters. The song peaked at number 19 on the U.S. Billboard Modern Rock Tracks chart. It was also placed at number 6 on Rolling Stone's list of the 100 Best Songs of 2008.[2]
The single releases of the song feature a cover of the song by garage punk musician Jay Reatard and a non-album song entitled "Bonfire Blondes" as B-sides, both of which are available on iTunes.[3][4] The song is included as a playable track in the video game Guitar Hero 5 and was used in Tony Hawk: Ride. Both the A side and B side album cover arts make use of a Houndstooth pattern.
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The first version of the music video, directed by Jess Holzworth, features actress and style icon Chlo Sevigny. The second version involves scenes of abstract imagery (most in black and white). There is film of Beck standing amidst many people dressed in white with white boxes on the heads. There is also film of mouths and eyes and a woman with an afro.
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Purpose: The expression of cytokine mRNA and their related transcription factors was examined in order to assess the effects of gamma radiation on the immune function of murine splenocytes.
Results: The mRNA level of interferon (IFN)-gamma, which is a Th1-type (T helper cell type 1) cytokine, was reduced after 3 h post-irradiation, whereas the interleukin (IL)-2 mRNA in the nave splenocytes had no significant changes within the 24 h after irradiation. Moreover, IFN-gamma and IL-2 mRNA expression in concanavalin A (Con A, 2.5 mug/ml) activated-splenocytes was significantly reduced by gamma irradiation. On the other hand, the mRNA level of the Th2 type (T helper cell type 2) cytokines, such as IL-4, IL-5 and IL-10, was increased both in nave and activated splenocytes, and pro-inflammatory cytokines were also rapidly induced in response to irradiation in nave splenocytes. Interestingly, gamma irradiation had no effect on transforming growth factor (TGF)-beta mRNA expression. Moreover, the mRNA levels of the leucine zipper trqnscription factor c-Maf and GATA binding protein-3 (GATA-3), which regulate IL-4 and IL-5 transcription, were found to have been up-regulated. However, the mRNA coding for interferon regulatory factor (IRF)-1, which is involved in IFN-gamma production, was reduced 6 h post-irradiation. The level of signal transducers and activators of transcription (Stat)-1 and Stat-4 phosphorylation, which are activated by IFN-gamma and IL-12, respectively, was significantly reduced by gamma irradiation, but IL-4 receptor mediated Stat-6 activation remained unchanged.
Conclusions: These results suggest that gamma irradiation may play a role in Th1 and Th2 cytokine expression, via regulation of the level of cytokine-mediators through transcriptional modulation and Stat signaling. These results are helpful to understand general profile of cytokine expression in response to gamma irradiation.
Interferon- (IFN-) plays a key role in activation of cellular immunity and subsequently, stimulation of antitumor immune-response. Based on its cytostatic, pro-apoptotic and antiproliferative functions, IFN- is considered potentially useful for adjuvant immunotherapy for different types of cancer. Moreover, it IFN- may inhibit angiogenesis in tumor tissue, induce regulatory T-cell apoptosis, and/or stimulate the activity of M1 proinflammatory macrophages to overcome tumor progression. However, the current understanding of the roles of IFN- in the tumor microenvironment (TME) may be misleading in terms of its clinical application.
Some researchers believe it has anti-tumorigenic properties, while others suggest that it contributes to tumor growth and progression. In our recent work, we have shown that concentration of IFN- in the TME determines its function. Further, it was reported that tumors treated with low-dose IFN- acquired metastatic properties while those infused with high dose led to tumor regression. Pro-tumorigenic role may be described through IFN- signaling insensitivity, downregulation of major histocompatibility complexes, upregulation of indoleamine 2,3-dioxygenase, and checkpoint inhibitors such as programmed cell death ligand 1.
Significant research efforts are required to decipher IFN--dependent pro- and anti-tumorigenic effects. This review discusses the current knowledge concerning the roles of IFN- in the TME as a part of the complex immune response to cancer and highlights the importance of identifying IFN- responsive patients to improve their sensitivity to immuno-therapies.
From a biological point of view, IFN- is a pleiotropic cytokine with antiviral, antitumor, and immunomodulatory functions. Hence, it plays an important role in coordinating both innate and adaptive immune response [6]. In an inflammatory environment, IFN- triggers the activation of the immune response and stimulates the elimination of pathogens; it also prevents over-activation of the immune system and tissue damage. This balance is maintained by complex mechanisms which are not yet fully understood [7, 8]. In the tumor microenvironment (TME), IFN- consistently orchestrates both pro-tumorigenic and antitumor immunity. IFN- acts as a cytotoxic cytokine together with granzyme B and perforin to initiate apoptosis in tumor cells [9, 10], but also enables the synthesis of immune checkpoint inhibitory molecules and indoleamine-2,3-dioxygenase (IDO), thus stimulating other immune-suppressive mechanisms [11,12,13]. Intriguingly, the contradictory biological and pathological effects of IFN- remain a focus area of study in literature. In this review, we summarize and explore the dualistic role of IFN- in regulation of tumor progression.
The production of IFN- is mainly regulated by natural killer (NK) and natural killer T (NKT) cells in innate immunity while CD8+ and CD4+ T-cells are major paracrine sources of IFN- during adaptive immune response [14]. These cells are stimulated by interleukins produced in situ, such as IL-12 [15], IL-15, IL-18, and IL-21 [16], tumor- or pathogen- secreted antigens [17], and partially by IFN- itself through an established positive feedback loop [3]. In an inflamed or tumorous tissue microenvironment, secreted proinflammatory cytokines bind to their receptors on IFN- producing cells and induce the activation of transcription elements such as members of the signal transducer and activator of transcription (STAT) family, mainly STAT4 [18], T-box transcription factor (T-bet) [19], activator protein 1 (AP-1) [20], or Eomes [21] which further drive IFN- production. It seems that the specific transcription factor that initiates IFN- transcription depends on the induction signal and cell type. For example, IL-12, an interleukin secreted by antigen-presenting cells (APCs) such as macrophages, dendritic cells (DCs), and B cells, induces the activation of STAT4 in CD4+ T-cells [22]. IL-12 binds to its receptor to enhance the activity of kinases from the Janus (JAK) family, namely JAK2 and TYK2. This drives the phosphorylation of STAT4 and prompts transcriptional functions. Furthermore, STAT4 increases the expression of IFN- directly or indirectly, through the activation of T-bet [23]. In addition, Liaskou et al. reported that a low dose of IL-12 enabled STAT4 phosphorylation in regulatory CD8+ T-cells, which stimulated IFN- production in patients with primary biliary cholangitis [22]. On the contrary, it has been shown that cell-surface receptors such as the T cell receptor on T-cells or the NK cell-activating receptor on NK cells, recognize existing antigens and activate tyrosine kinases of the Src family. Subsequently, Src kinases stimulate mitogen-activated protein kinases (MAPKs), mostly extracellular signal-regulated kinases (ERK) and p38, which further induce Fos and Jun expression. Additionally, these transcription factors upregulate IFN- expression and stimulate its synthesis [24]. The secreted IFN- binds to its receptor (IFNGR) present on a variety of cells to regulate the immune response. Notably, IFN- may also stimulate APCs to secrete more IL-12 which triggers the re-activation of the IFN- production cycle. This is known as the positive feedback loop of IFN- synthesis and is detected in both tumor and inflamed environments [25].
Nave CD4+ T-cells differentiate into helper T-cells, Th1 and Th2, in response to certain cytokines secreted during inflammation [26]. In such an environment, CD4+ Th1 cells are the main source of IFN- and are defined by the secretion of signature cytokines, namely IL-12, IL-2, and IFN-, as well as T-bet expression [27, 28]. T-bet, a transcription factor of the T-box family encoded by the TBX21 gene, is an important promoter of IFN- synthesis. Its expression was initially observed in Th1 cell clones after stimulation with the anti-CD3 antibody; the same effect was absent in Th2 cells. The expression level of T-bet was correlated with the IFN- production in Th1 and NK cells but not in Th2 clones. In addition, the retroviral transduction of T-bet to Th2 differentiated cells could reprogram them into Th1 cells, as observed by initiation of IFN- production, further confirming the connection between T-bet and cytokine secretion [29]. 152ee80cbc