Journal articles on the topic 'CSG Rendering'

In the Constructive Solid Geometry (CSG) representation a geometric object is described as the hierarchical combination of a number of primitive shapes using the operations union, intersection, subtraction, and exclusive-union. This hierarchical description defines an expression tree, T, called the CSG tree, with leaves associated with primitive shapes, internal nodes associated with operations, and whose "value" is the geometric object. Evaluation of CSG trees is an important computation that arises in many rendering and analysis problems for geometric models, with ray shooting (also known as "ray casting") being one of the most important. Given any CSG tree T, which may be unbalanced, we show how to convert T into a functionally-equivalent binary tree, D, that is balanced. We demonstrate the utility of this conversion by showing how it can be used to improve the worst-case running time for ray shooting against a CSG model from O(n2) to O(n log n), which is optimal. In addition, the practicality of our method has been demonstrated in experimental benchmarking tests using the BRL-CAD package.

Raster comic would result in bad quality while zooming in/out. Different approaches were proposed to convert comic into vector format to resolve this problem. The authors have proposed methods to vectorize comic contents to provide not only small SVG file size and rendering time, but also better perceptual quality. However, they do not process texture in the comic images. In this paper, the authors improve their previously developed system to recognize texture elements in the comic and use these texture elements to provide better compression and faster rendering time. They propose texture segmentation techniques to partition comic into texture segments and non-texture segments. Then, the <pattern> element of SVG is applied to represent texture segments. Their method uses CSG (Composite Sub-band Gradient) vector as texture descriptor and uses SVM (Support Vector Machine) to classify texture area in the comic. Then, the ACM (Active Contour Model) combining with CSG vectors is introduced to improve the segmentation accuracy on contour regions. Experiments are conducted using 150 comic images to test the proposed method. Results show that the space savings of our method is over 66% and it can utilize the reusability of SVG syntax to support comic with multiple textures. The average rendering time of the proposed method is over three times faster than the previous methods. It lets vectorized comics have higher performance to be illustrated on modern e-book devices.

Abstract Background: Fragile X syndrome is caused by the expansion of a CGG trinucleotide repeat at the 5′ untranslated region of the fragile X mental retardation 1 gene (FMR1). When expanded to &gt;200 repeats (full mutation), the repeat region and the adjacent promoter CpG island become hypermethylated, rendering FMR1 transcriptionally inactive. Conventional molecular diagnosis of fragile X syndrome involves determination of the CGG repeat number by Southern blot analysis. Methods: A homogeneous methylation-specific melting curve analysis (MS-MCA) assay for methylation status of the FMR1 promoter region was developed on the LightCycler platform. Genomic DNA was treated with sodium bisulfite, and a region containing 8 CpG sites was amplified in the presence of SYBR Green I, using primers that do not differentiate between methylated and unmethylated FMR1 molecules. After amplification, the samples were melted at 0.05 °C/s, and fluorescence melting curves were recorded. We studied samples, previously characterized by Southern blot analyses, from 10 female and 10 male donors with normal numbers of CGG trinucleotide repeats, 9 male donors who were premutation carriers, 4 male donors who carried both a premutation and a full mutation, and 25 patients with fragile X syndrome. Results: Samples from all 20 male patients with fragile X syndrome showed a high melting peak corresponding to fully methylated FMR1, whereas samples from healthy males showed a single low melting peak corresponding to unmethylated FMR1. Of 24 samples from affected males, 9 (38%) showed 2 melting peaks, suggesting that cellular methylation mosaicism is common in fragile X syndrome. Conclusions: MS-MCA allows rapid and reliable identification of fragile X syndrome in male patients.

ABSTRACT Despite substantial progress in understanding the mechanism by which expanded CTG/CAG trinucleotide repeats cause neurodegenerative diseases, little is known about the basis for repeat instability itself. By taking advantage of a novel phenomenon, we have developed a selectable assay to detect contractions of CTG/CAG triplets. When inserted into an intron in the APRT gene or the HPRT minigene, long tracts of CTG/CAG repeats (more than about 33 repeat units) are efficiently incorporated into mRNA as a new exon, thereby rendering the encoded protein nonfunctional, whereas short repeat tracts do not affect the phenotype. Therefore, contractions of long repeats can be monitored in large cell populations, by selecting for HPRT+ or APRT+ clones. Using this selectable system, we determined the frequency of spontaneous contractions and showed that treatments with DNA-damaging agents stimulate repeat contractions. The selectable system that we have developed provides a versatile tool for the analysis of CTG/CAG repeat instability in mammalian cells. We also discuss how the effect of long CTG/CAG repeat tracts on splicing may contribute to the progression of polyglutamine diseases.

This paper situates the Sub-Saharan African state amidst the conflictual interface between the forces of political (Note 1) and economic globalization (Note 2) that have been ushered in the state milieu by neo-liberalism (Note 3). The paper argues that states are situated in an imperialistic globalization with capitalistic economic extirpation as central concern and social justice as a peripheral one. This categorically explicates the persistence of globalised economies and localized oppressive state apparatuses, ideologies and practices. The paper also contends that the forces of economic globalization have superimposed the cultural mantra in the Sub-Saharan Africa state milieu, rendering it virtually impossible to pursue a Rights Based Approach to Development (RBAD). The apparent assault by this globalization from above (economic globalization), continues almost unabated due to absence of an afro centric globalization from below to mitigate the homogenizing effects of economic globalization. Worse still, the inability of political globalization to check the daunting implications of economic globalization using a human rights antidote and the consequent slumber of the glocalisation dialectic in the African state locale explicate the problematic of Africa in the wake of erosion from above (global pillage) and devolution from below.

Bioinformaticians routinely analyse vast amounts of information held both in large remote databases and in flat data files hosted on local machines. The contemporary toolkit available for this purpose consists of anad hoccollection of data manipulation tools, scripting languages and visualization systems; these must often be combined in complex and bespoke ways, the result frequently being an unwieldy artefact capable of one specific task, which cannot easily be exploited or extended by other practitioners. Owing to the sizes of current databases and the scale of the analyses necessary, routine bioinformatics tasks are often automated, but many still require the unique experience and intuition of human researchers: this requires tools that support real-time interaction with complex datasets. Many existing tools have poor user interfaces and limited real-time performance when applied to realistically large datasets; much of the user's cognitive capacity is therefore focused on controlling the tool rather than on performing the research. The UTOPIA project is addressing some of these issues by building reusable software components that can be combined to make useful applications in the field of bioinformatics. Expertise in the fields of human computer interaction, high-performance rendering, and distributed systems is being guided by bioinformaticians and end-user biologists to create a toolkit that is both architecturally sound from a computing point of view, and directly addresses end-user and application-developer requirements.

AbstractThe present study describes how Swedish Sign Language (SSL) interpreters systematically use signing space and movements of their hands, arms and body to simultaneously layer iconic expressions of metaphors for differences and for time, in ways previously not described. This is analyzed as the interpreters embodying metaphors, and each of the conceptual metaphors they embody seems to be expressed in a distinct manner not noted before in accounts of the structure of signed languages. Data consists of recordings of Swedish-SSL interpreting by native SSL signers. Rendering spoken Swedish into SSL, these interpreters produce complex sequences making abundant use of the circumstance that in signed language you can express several types of information simultaneously. With little processing time, they produce iconic expressions, frequently using several underlying conceptual metaphors to simultaneously layer information. The interpreters place individual signs in relation to time lines in order to express metaphorical content related to time, and use movement’s of their bodies to express comparisons and contrasts. In all of the analyzed sequences, the interpreters express the metaphor difference-between-is-distance-between. In addition, they layer metaphors for difference and time simultaneously, in some instances also expressing the orientational metaphor pair more-is-up and less-is-down at the same time.

With the development of 3D rendering techniques, people can create photorealistic computer graphics (CG) easily with the advanced software, which is of great benefit to the video game and film industries. On the other hand, the abuse of CGs has threatened the integrity and authenticity of digital images. In the last decade, several detection methods of CGs have been proposed successfully. However, existing methods cannot provide reliable detection results for CGs with the small patch size and post-processing operations. To overcome the above-mentioned limitation, we proposed an attention-based dual-branch convolutional neural network (AD-CNN) to extract robust representations from fused color components. In pre-processing, raw RGB components and their blurred version with Gaussian low-pass filter are stacked together in channel-wise as the input for the AD-CNN, which aims to help the network learn more generalized patterns. The proposed AD-CNN starts with a dual-branch structure where two branches work in parallel and have the identical shallow CNN architecture, except that the first convolutional layer in each branch has various kernel sizes to exploit low-level forensics traces in multi-scale. The output features from each branch are jointly optimized by the attention-based fusion module which can assign the asymmetric weights to different branches automatically. Finally, the fused feature is fed into the following fully-connected layers to obtain final detection results. Comparative and self-analysis experiments have demonstrated the better detection capability and robustness of the proposed detection compared with other state-of-the-art methods under various experimental settings, especially for image patch with the small size and post-processing operations.

Abstract BACKGROUND: Karyotype analysis of metaphase cells for discovering genome-wide cytogenetic abnormalities has played an important role in prognosis and counseling of patients with chronic lymphocytic leukemia (CLL). Due to the low proliferative rate of CLL B cells, karyotype analysis has been of limited clinical utility in this disease. Thus, fluorescence in situ hybridization (FISH) on interphase cells has replaced karyotype analysis for the assessment of recurrent genetic changes in CLL. Recently, immunostimulatory CpG-oligodeoxynucleotides (CpG) have been shown to induce primary CLL B cell proliferation via engagement of toll-like receptor 9 (TLR9), thereby rendering karyotype analysis feasible and providing for a useful and reliable method to discover new cytogenetic abnormalities in CLL B cells. However, we and others have shown that CpG stimulation of CLL and normal B cells also induces robust expression of activation induced cytidine deaminase (AID), a mutagenic enzyme that is linked to the development of cytogenetic abnormalities. It is therefore plausible that cytogenetic abnormalities observed following CpG stimulation of CLL B cells may not reflect de novo abnormalities but rather reflect CpG induced-AID mediated cytogenetic alterations. We began to address this possibility by assessing the effects of CpG stimulation on the karyotypes of normal blood B cells. HYPOTHESIS: Since CpG stimulation induces AID expression in CLL and normal B cells, we hypothesize that: robust B cell activation by CpG could result in cytogenetic abnormalities thereby contributing to lymphomagenesis; and if CpG induces cytogenetic abnormalities that are linked to disease initiation and/or progression, such information would be of great value in the interpretation of cytogenetic data obtained from CpG-stimulated CLL B cells. METHODS: We performed interphase FISH analysis on freshly isolated blood B cells, and metaphase karyotype analysis on CpG stimulated B cells from 17 healthy blood donors. Pure (&gt;98%) B cells obtained by negative selection, were hybridized at isolation with a probe set to identify deletion 6q, 11q, 13q, and 17p, trisomy 12, and IGH gene rearrangements, and cells were also stimulated for 5 days with 10 μg/ml CpG (CpG 2006, synthesized in-house) plus IL-2 and IL-15 for metaphase analysis. At least 20 post-CpG metaphase spreads were analyzed for each sample and abnormalities were considered clonal using the accepted convention (gains or translocations are present in two or more cells and loss present in at least 3 cells). The expression of AID in the B cells pre- and post-CpG stimulation was assessed by RT-PCR. RESULTS: FISH analysis of freshly isolated B cells showed that all 17 subjects were normal. After CpG stimulation, all samples examined exhibited strong AID expression as revealed by RT-PCR. By karyotype analysis, none of the 17 CpG stimulated samples showed evidence of clonal abnormalities. However, one or more nonclonal chromosomal abnormalities were observed in 7 out of 17 (41.2%) samples. Among those 7 samples, 4 samples had 1 abnormal metaphase out of a minimum of 20 examined while the other 3 samples exhibited two or more cells, each with distinct abnormalities. Some of those nonclonal abnormalities have also been observed in CLL (i.e., trisomy 3, trisomy 12 and 14q32 rearrangements). This is a much higher incidence of nonclonal abnormalities than has been seen with peripheral blood cells cultured by other methods. CONCLUSION: Our data have significance for the biology of CLL and for clinical practice. First, our data suggest that signaling through TLR9, and perhaps other receptors that likewise induce robust B cell AID expression, may represent a natural mechanism by which B lineage cells acquire chromosomal abnormalities during normal immune responses that may predispose toward neoplastic transformation. Second, given that none of the CpG-induced metaphases in normal B cells resulted in clonal abnormalities in the 5 day timeframe, our data also validate the clinical utility of CpG as a valuable tool for the cytogenetic analysis of CLL B cells since only clonal abnormalities are currently scored. However, it remains possible that non-clonal abnormalities seen in CpG-stimulated CLL B cells may be relevant to the disease process if future work shows that CpG stimulation uncovers recurring non-clonal defects of chromosomes/genes associated with tumorigenic events.

A single treatment with a CpG-containing immunostimulatory DNA sequence (ISS) given before allergen challenge can inhibit T helper type 2 cell (Th2)–mediated airway responses in animal models of allergic asthma; however, the mechanism of this inhibition remains largely undefined. Here, we demonstrate that airway delivery of ISS before allergen challenge in Th2-primed mice acts in two distinct ways to prevent the allergic responses to this challenge. The first is to prevent induction of cytokines from allergen-specific Th2 cells, as demonstrated by the nearly complete inhibition of Th2 cytokine production, Th2-dependent functional responses, and gene induction patterns. ISS inhibits the Th2 response by rendering lung antigen-presenting cells (APCs) unable to effectively present antigen to Th2 cells, but not to Th1 cells. This loss of APC function correlates with a reduced expression of costimulatory molecules, including programmed cell death ligand (PD-L)1, PD-L2, CD40, CD80, CD86, and inducible T cell costimulator, and of major histocompatibility complex class II on CD11c+APCs from the airways of ISS-treated mice. The second important action of ISS is inhibition of immunoglobulin E–dependent release of Th2 cytokines, especially interleukin 4, from basophils and/or mast cells in the airways of Th2-primed mice. Thus, inhibition by ISS of allergic responses can be explained by two novel mechanisms that culminate in the inhibition of the principal sources of type 2 cytokines in the airways.

Abstract Clonal hematopoiesis of indeterminate potential (CHIP) is a clonal disorder characterized by preleukemic mutations and increases in prevalence during aging. Infrequently CHIP progresses to hematological cancer implying that preleukemic mutations subtly affect leukemogenesis but a mechanistic explanation is lacking. Exceedingly, preleukemic mutations are acquired in genes encoding for DNA methylation modifiers, predominantly in DNMT3A and members of the active DNA demethylation pathway. DNMT3A encodes a de novo methyltransferase establishing 5-methylcytosine (5mC) and mutations in this gene are linked to impaired DNA methylation and DNA damage sensing. Active DNA demethylation is carried out by two independent pathways (Figure 1A). The oxidation active repair (AOAR) pathway converts 5mC to DNA demethylation derivates which are cleaved by the DNA glycosylase TDG. The deamination pathway deaminates 5mC introducing a T/G mismatch which is cleaved by the DNA glycosylases MBD4 and TDG. Importantly, ineffective T/G mismatch repair results in C>T mutations at CpGs. Strikingly, recent studies revealed that the genomes of acute myeloid leukemia (AML) patients have a preponderance for C>T mutations at CpGs, potentially linking this mutational process to the deamination pathway. Here we present data revealing a specific mechanism by which DNMT3A gene mutations may enhance leukemogenesis through the deregulation of the active DNA demethylation pathway. A detailed understanding on the effects of DNA methylation modifier mutations was obtained from a single AML patient for whom we carried out whole exome sequencing on diagnostic and relapse specimens. At diagnosis the patient presented with 331 somatic mutations from which 324 where C>T mutations (97.8%) and at relapse his leukemia had acquired 386 somatic mutations from which 384 where C>T mutations (99.5%), which almost all (>95%) were in CpGs. We superimposed the somatic mutations on the DNA demethylation pathways to understand the pervasiveness of this mutational process in this AML patient. We detected a R132C IDH1 mutation at diagnosis and relapse effectively impairing the AOAR pathway. Thus, only ineffective T/G mismatch repair by the deamination pathway could confer this mutational pattern. Strikingly, we observed a homozygous MBD4 mutation rendering the protein catalytically inactive. However, we could not detect genetic lesions perturbing TDG. Recent studies demonstrated that DNMT3A potentiates TDG activity through interaction. Consistent with this finding the patient presented at diagnosis the hotspot R882C DNMT3A mutation while at relapse his leukemia presented with the R635W, R668C, R882C and A884V DNMT3A mutations. We investigated whether mutant DNMT3A systematically attenuates TDG activity through glycosylase activity assays with recombinant proteins. We demonstrated that incrementing wildtype DNMT3A concentration increase the TDG activity towards T/G-mismatches. In contrast, we found that recombinant DNMT3A with mutations at R668C, R882C and A884V rapidly decrease TDG activity with increasing concentrations, while DNMT3A R635W affected TDG activity to a lesser extent. Importantly, wildtype DNMT3A only overcomes the negative effects of mutant DNMT3A on TDG activity at high concentration implying a dominant negative effect of mutant DNMT3A. We subsequently analyzed a larger cohort of AML cases. Targeted sequencing of 750 AML cases and public data from the Cancer Genome Atlas revealed a specific AML subgroup characterized by biallelic DNMT3A mutations, with concurrent TET2, IDH1 or IDH2 mutations, but lacking NPM1 mutations. Our data suggest that impairment of the AOAR pathway combined with the loss of wildtype DNMT3A attenuates TDG activity and greater CpG mutability (Figure 1B). Notably, multivariate analysis revealed that biallelic DNMT3A mutations serve as an independent marker for poor prognosis (p=3.89x10-5). In summary, these studies provide strong evidence for a novel mechanism by which mutant DNMT3A enhances CpG mutagenesis through attenuation of the DNA glycosylase TDG, frequently in combination with AOAR pathway impairment, a mutational pattern frequently observed in AML. Therefore preleukemic mutations in CHIP, like those frequently observed in DNMT3A, could play a pivotal role by increasing the likelihood of acquiring crucial secondary genetic events by attenuating DNA repair at CpGs. Disclosures No relevant conflicts of interest to declare.

Abstract All-trans retinoic acid (ATRA) signaling pathway is of critical importance for optimal myelomonocytic differentiation and its disruption by translocations of the RARα gene leads to acute promyelocytic leukemia (APL). APL associated fusion oncoproteins, such as PML-RARα and PLZF-RARα, function through recruitment of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), thus promoting an inactive chromatin state and leading to repression of RARα target genes. Recently, we demonstrated that up-regulation of RARα2 expression by ATRA directly correlates with differentiation in non-APL AML cells. Treatment of ATRA non-responsive cells with the demethylating agent 5-Aza-2′-deoxycytidine (decitabine) restores RARα2 expression and differentiation response to ATRA in different AML subtypes, suggesting abnormal epigenetic changes as a possible mechanism underlying silencing of RARα2 and contributing to a differentiation deficit in these cells. Here we compared the methylation status of ATRA-inducible RARα2 and constitutive RARα1 promoters in 5 human AML cell lines and in normal human CD11b+/CD33+ leukocytes (NLs) by sequencing their respective bisulfite modified CpG islands. Whereas the CpG-island of the RARα2 promoter was completely methylated in all AML samples, it was not methylated in NLs nor in a control preB cell line, NALM-6. The methylation status of the RARα2 promoter directly correlates with the RARα2 expression level, which was shown by real-time RT-PCR to be 100–1000 fold higher in NLs or NALM-6 cells than in AML cell lines. Expression of RARα2 in human primary AML cells was found to be as low as in AML cell lines. In contrast, RARα1 promoter was not methylated in any of the samples and RARα1 expression levels were similar in AML cells and NLs. We have previously shown that stimulation of AML cell differentiation by ATRA and G/GM-CSF (GFs) is associated with a 10 fold induction of RARα2 expression through direct effects on receptor activity. We now show that pre- or co-treatment with decitabine results in up to 100 fold further increase in RARα2 expression levels, rendering the RARα2 mRNA levels similar to these observed in NLs. This synergism in RARα2 induction is paralleled by marked enhancement of leukemic cell differentiation. These results highlight the potential therapeutic use of epigenetic modifiers like decitabine, which may relieve the repression of aberrantly silenced genes required for cellular maturation and amplify the effects of differentiation inducers like ATRA and GFs in AML.

Abstract BACKGROUND The WHO classification 2021 includes multiple molecular markers for routine diagnostics in addition to histology. Sequencing setup for complete molecular profiling requires considerable investment, while batching samples for sequencing and methylation profiling can delay turnaround time. We introduce RAPID-CNS2, a nanopore adaptive sequencing pipeline that enables comprehensive mutational, methylation and copy number profiling of CNS tumours with a single third generation sequencing assay. It can be run for single samples and offers highly flexible target selection requiring no additional library preparation. MATERIAL AND METHODS Utilising ReadFish, a toolkit enabling targeted nanopore sequencing, we sequenced DNA from 22 diffuse glioma patient samples on a MinION device. Target regions comprised our Heidelberg brain tumour NGS panel and pre-selected CpG sites for methylation classification by an adapted random forest classifier. Pathognomonic alterations, copy number profiles, and methylation classes were called using a custom bioinformatics pipeline. Results were compared to their corresponding NGS panel-seq and EPIC array outputs. RESULTS Complete concordance with the EPIC array was found for copy number profiles from RAPID-CNS2. 94% pathognomonic mutations were congruent with NGS panel-seq. MGMT promoter status was correctly identified in all samples. Methylation families were detected with 96% congruence. Among the alterations decisive for rendering a classification-compatible integrated diagnosis, 97% of the alterations were consistent over the entire cohort (completely congruent in 19/22 cases and sufficient for unequivocal diagnosis in all). CONCLUSION RAPID-CNS2 provides a swift and highly flexible alternative to conventional NGS and array-based methods for SNV/Indel analysis, detection of copy number alterations and methylation classification. The turnaround time of ~4 days can be further shortened to &lt;12h by altering target sizes. It offers a low-capital approach that would be cost-efficient for low throughput settings and invaluable in cases requiring immediate diagnoses.

Abstract Chronic lymphocytic leukemia (CLL) cells rely on signals from the microenvironment to for cell activation, proliferation and survival. Microarray analysis of CLL cells harvested from patient-matched lymph node and peripheral blood demonstrated an up-regulation of B-cell receptor (BCR) signaling in the tissue microenvironment (Herishanu, Blood 2011). Concurrent with increased BCR signaling a dynamic increase in NF-κB signaling was also noted in the activated CLL cells in the tissue microenvironment (Herishanu, Blood 2011). As NF-κB can be activated downstream of multiple signaling pathways, in addition to the BCR, we sought to determine the role of alternative pathways on NF-κB activation. In gene expression analysis of CD19+ selected CLL cells, we found that in addition to an increase in BCR signaling the Toll-like receptor (TLR) signaling pathway was also significantly up-regulated in CLL cells in the lymph node microenvironment compared to circulating CLL cells. Activation of TLR signaling can cooperate with BCR signaling to overcome anergy and promote the expansion of auto-reactive B-cells (Leadbetter, Nature 2002). In addition, TLR signaling can induce proliferation of CLL cells and upregulates co-stimulatory molecules that may make CLL cells more effective antigen presenting cells. The latter effect has been explored as a therapeutic strategy to enhance the efficacy of immunotherapy of CLL by rendering CLL cells more susceptible to attack by cytotoxic T-cells (Spaner and Masellis, Leukemia 2007). We hypothesize that inhibition of TLR signaling could contribute directly to anti-leukemic effects by inhibiting survival and proliferation pathways. To test the effect of TLR signaling in CLL, CLL PBMCs were stimulated in vitro with a CpG oligonucleotide, which activates TLR9, for 6 hours. Increased pIκBα expression along with significant increases in pSTAT3 (P=0.001), IL-10 production (P=0.008) and up-regulation of the cell surface activation markers CD54, CD69 and CD86 (P<0.001) were observed, consistent with activation of TLR signaling. In order to evaluate the effect of inhibiting TLR signaling on CLL cells, we utilized an inhibitor of IRAK1/4 (EMD Chemicals), which acts directly downstream of MyD88. As expected, inhibition of IRAK1/4 significantly reduced TLR signaling in CpG stimulated CLL cells, resulting in decreased NF-κB signaling, IL-10 secretion (P=0.03) and phosphorylation of STAT3 (P<0.001) in drug treated compared to vehicle treated cells. Concurrently, inhibition of proliferation (as measured by Ki67) and tumor cell activation (CD69 and CD86 expression) was observed (P <0.05), demonstrating a direct anti-leukemic effect. Recently, the BTK inhibitor ibrutinib was shown to be clinically active in Waldenstrom's macrogloublinemia (WM), a chronic B-cell malignancy not dissimilar to CLL that is characterized by mutations in the TLR adaptor MyD88 (Treon, NEJM 2012; Treon, NEJM 2015). We therefore investigated whether ibrutinib could inhibit TLR signaling in CLL cells. Indeed, even at doses as low as 100nM, ibrutinib significantly inhibited CpG dependent activation of NF-κB signaling (P<0.05), downstream secretion of IL-10 (P<0.05) and phosphorylation of STAT3 (P<0.01). Additionally, proliferation (Ki67) and cellular activation induced by CpG were inhibited by ibrutinib treatment (P<0.05). Notably, both the inhibition of TLR signaling and the anti-tumor effect of ibrutinib at 100nM was comparable to inhibition achieved with 10µM of the IRAK1/4 inhibitor. In summary, TLR signaling is engaged in CLL cells in the lymph node microenvironment and upregulates proliferation and survival pathways. Ibrutinib appears to be as effective as a direct IRAK inhibitor in blocking TLR signaling in CLL cells, suggesting that treatment with ibrutinib is sufficient to inhibit both BCR and TLR signaling. This work was supported by the Intramural Research Program of National Heart Lung and Blood Institute of the National Institutes of Health. Disclosures Wiestner: Pharmacyclics: Research Funding.

The present article is the continuation of the text published in issue 12 of “Notes Muzyczny” from December 2019. This paper is devoted to discussing technical issues connected with designing and constructing Opus 1 Portative built by the author; it also touches on practical performance aspects of portative music. The instrument fully designed and constructed by the author is a one-octave portative with stoppedwoodenpipesanditssoundrangeisc1-c2withanoptiontoretunecs1intobandb 1 into cs2 or d2. The default tuning pitch is a=440Hz but it can be altered within 415-465Hz; the temperament may also be freely changed. One wedge bellow placed at the back of the instrument is used for bellow treading. A leather belt worn over the shoulder and the low weight of the construction allow for playing the instrument not only while sitting but also in a standing position. As compared to similar instruments, this portative has more extended case which fully covers the ends of pipes. Opus 1 Portative was built thanks to a few years of research studies and technical work of the author covering the construction of organ components and independent attempts to miniaturise them for the purpose of construction of this specific instrument. Thanks to that, in order to build Opus 1 the author used a few original solutions – e.g. the way of gluing top corners of the bellow, the way of regulating the airflow through the foot of the pipe or the technique of attaching the handle to the stopper of a stopped pipe, with the limited space above its body. The majority of experimental solutions brought satisfactory results and for the remaining ones Piotr Dziewiecki managed to find ways to overcome the difficulties which arose. The author uses the instrument in his own performance practice both for solo music and for playing in ensembles. The portative is very useful for both fields, ensuring wide dynamics and articulation-related capacities. They are connected with an option to very precisely control the pressure of air powering the pipes and with their way of blowing. Its characteristic sound, warm and full of depth, brings associations with human voice. Thanks to that, vocal-and- instrumental music performed on it, with the portative player rendering the singer’s part, sounds good.

Abstract Introduction: Multiple myeloma (MM) is a neoplastic disorder that is characterized by clonal proliferation of plasma cells in the bone marrow (BM). Despite the initial efficacious treatment, MM patients often become refractory to common anti-MM drugs, therefore novel therapies are in need. Pan-histone deacetylase (HDAC) inhibitor panobinostat exerts multiple cytotoxic actions in MM cells in vitro, and was approved for the treatment of relapsed/refractory MM in combination with bortezomib and dexamethasone. Although having promising anti-MM properties, panobinostat lacks therapeutic activity as monotherapy. The aim of the current study was to elucidate the mechanisms underlying MM resistance to panobinostat and to define strategies to overcome it. Results: Panobinostat at the low concentrations (IC50 5-30 nM) suppressed the viability in MM cell lines (n=7) and primary CD138+ cells from MM patients (n=8) in vitro. Sensitivity to panobinostat correlated with reduced expression of chemokine receptor CXCR4, while overexpression of CXCR4 or its ligand CXCL12 in RPMI8226 and CAG MM cell lines significantly (p<0.001) increased their resistance to panobinostat, pointing to the role of the CXCR4 axis in HDACi response. Notably, similar expression levels of class I HDACs (HDAC1-3) were detected in MM cells with either low or high CXCR4. Interaction with BM stromal cells that represent the source of CXCL12 also protected MM cells from panobinostat-induced apoptosis, further strengthening a role for CXCR4 downstream pathway. Decreased sensitivity to cytotoxic effect was concomitant with reduced histone (H3K9 and H4K8) acetylation in response to panobinostat treatment. In addition, resistance to HDACi was associated with the reversible G0/G1 cell growth arrest, whereas sensitivity was characterized by apoptotic cell death. Analysis of intra-cellular signaling mediators involved in CXCR4-mediated HDACi resistance revealed the pro-survival AKT/mTOR pathway to be regulated by both CXCR4 over-expression and interaction with BMSCs. Combining panobinostat with mTOR inhibitor everolimus abrogated the resistance and induced synergistic cell death of MM cell lines and primary MM cells, but not of normal mononuclear cells (CI<0.4). This effect was concurrent with the increase in DNA double strand breaks, histone H2AX phosphorylation, loss of Dψm, cytochrome c release, caspase 3 activation and PARP cleavage. The increase in DNA damage upon combinational treatment was not secondary to the apoptotic DNA fragmentation, as it occurred similarly when apoptosis onset was blocked by caspase inhibitor z-VAD-fmk. Kinetics studies also confirmed that panobinostat-induced DNA damage preceded apoptosis induction. Strikingly, combined panobinostat/everolimus treatment resulted in sustained DNA damage and irreversible suppression of MM cell proliferation accompanied by robust apoptosis, in contrast to the modest effects induced by single agent. Gene expression analysis revealed distinct genetic profiles of single versus combined exposures. Whereas panobinostat increased the expression of cell cycle inhibitors GADD45G and p21, co-treatment with everolimus abrogated the increase in p21 and synergistically downregulated DNA repair genes, including RAD21, Ku70, Ku80 and DNA-PKcs. Furthermore, combined treatment markedly decreased both mRNA and protein expression of anti-apoptotic factors survivin and BCL-XL, checkpoint regulator CHK1, and G2/M-specific factors PLK1, CDK1 and cyclin B1, therefore suppressing the DNA damage repair and inhibiting mitotic progression. Given the anti-apoptotic role of p21, the synergistic lethal effect of everolimus could be attributed to its ability to suppress p21 induction by panobinostat ensuing the shift in the DNA damage response toward apoptosis. Conclusions: Collectively, our findings indicate that CXCR4/CXCL12 activity promotes the resistance of MM cells to HDACi with panobinostat through mTOR activation. Inhibition of mTOR by everolimus synergizes with panobinostat by simultaneous suppression of p21, G2/M mitotic factors and DNA repair machinery, rendering MM cells incapable of repairing accumulated DNA damage and promoting their apoptosis. Our results unravel the mechanism responsible for strong synergistic anti-MM activity of dual HDAC and mTOR inhibition and provide the rationale for a novel therapeutic strategy to eradicate MM. Disclosures No relevant conflicts of interest to declare.

This paper presents an infrastructure that integrates a haptic interface into a mainstream computer-aided design (CAD) system. A haptic interface, by providing force feedback in human-computer interaction, can improve the working efficiency of CAD/computer-aided manufacturing (CAM) systems in a unique way. The full potential of the haptic technology is best realized when it is integrated effectively into the product development environment and process. For large manufacturing companies this means integration into a commercial CAD system (Stewart, et al., 1997, “Direct Integration of Haptic User Interface in CAD Systems,” ASME Dyn. Syst. Control Div., 61, pp. 93–99). Mainstream CAD systems typically use constructive solid geometry (CSG) and boundary representation (B-Rep) format as their native format, while internally they automatically maintain triangulated meshes for graphics display and for numerical evaluation tasks such as surface-surface intersection. In this paper, we propose to render a point-based haptic force feedback by leveraging built-in functions of the CAD systems. The burden of collision detection and haptic rendering computation is alleviated by using bounding spheres and an OpenGL feedback buffer. The major contribution of this paper is that we developed a sound structure and methodology for haptic interaction with native CAD models inside mainstream CAD systems. We did so by analyzing CAD application models and by examining haptic rendering algorithms. The technique enables the user to directly touch and manipulate native 3D CAD models in mainstream CAD systems with force/touch feedback. It lays the foundation for future tasks such as direct CAD model modification, dynamic simulation, and virtual assembly with the aid of a haptic interface. Hence, by integrating a haptic interface directly with mainstream CAD systems, the powerful built-in functions of CAD systems can be leveraged and enhanced to realize more agile 3D CAD design and evaluation.

Spatial statistics and experimental design are among the most important topics students in the environmental and ecological sciences learn and utilize throughout their careers. These topics are also among the most difficult for students to learn, often due to the use of contrived data sets that present simplified and unrealistic scenarios that fail to engage students in higher level thinking. One way to engage students in higher level thinking is to use an inquiry-based pedagogical framework. The use of inquiry as a pedagogical approach should be instinctive for most scientists, as it mimics how science is conducted, yet most instructors continue to use lecture-based, textbook-driven instructional formats. This type of approach is efficient in covering material, but it suffers in its ability to engage students or enhance learning. Using a Bigfoot data set in an inquiry-based framework, students in a cross-listed graduate/undergraduate statistics class learned ordinary least squares regression and geographically weighted regression techniques. These techniques are among the most frequently applied analyses in the natural sciences. The use of a Bigfoot data set engaged students’ interest, rendering the prospect of learning regression topics as an emergent property of their interest and engagement. This approach also has an additional benefit in that students learned not only key statistical concepts but also learn how to self-diagnose deficiencies with their models as well as how to identify strategies to overcome these deficiencies. We hope that both instructors and students in graduate and undergraduate statistics or spatial modeling courses find this case study, and included data sets, a useful and interesting approach to teach and learn regression and spatial regression.

Abstract Background miR-1250 is localised to the second intron of AATK at chromosome 17q25. As a CpG island is present at the putative promoter region of its host gene, AATK, we postulated that the intronic miR-1250-5p is a tumor suppressor miRNA co-regulated with its host gene, AATK, by promoter DNA methylation in non-Hodgkin’s lymphoma (NHL). Methods AATK/miR-1250 methylation was studied in healthy controls, including ten normal peripheral blood buffy coats and eleven normal tonsils, ten lymphoma cell lines, and 120 primary lymphoma samples by methylation-specific PCR (MSP). The expression of miR-1250-5p and AATK was investigated by quantitative real-time PCR. Tumor suppressor properties of miR-1250-5p were demonstrated by over-expression of precursor miR-1250-5p in lymphoma cells. The target of miR-1250-5p was verified by luciferase reporter assay. Results AATK/miR-1250 methylation was absent in healthy peripheral blood and tonsils, but detected in five (50%) NHL cell lines. AATK/miR-1250 methylation correlated with repression of miR-1250-5p and AATK in NHL cell lines. In completely methylated SU-DHL-6 and SUP-T1 cells, treatment with 5-AzadC led to promoter demethylation and re-expression of both miR-1250-5p and AATK. In primary lymphoma samples, AATK/miR-1250 was frequently methylated in B-cell lymphoma (n = 41, 44.09%) and T-cell lymphoma (n = 9, 33.33%) with a comparable frequency (P = 0.318). In SU-DHL-6 and SU-DHL-1 cells, restoration of miR-1250-5p resulted in decreased cellular proliferation by MTS assay, increased cell death by trypan blue staining and enhanced apoptosis by annexin V-PI assay. Moreover, MAPK1 and WDR1 were verified as direct targets of miR-1250-5p by luciferase assay. In 39 primary NHLs, miR-1250-5p expression was shown to be inversely correlated with each of MAPK1 (P = 0.05) and WDR1 (P = 0.031) by qRT-PCR. Finally, in SU-DHL-1 cells, overexpression of miR-1250-5p led to repression of MAPK1 and WDR1 at both transcript and protein levels, with downregulation of phospho-ERK2 by Western-blotting and inhibition of SDF-1-dependent cell migration by transwell assay. Conclusions miR-1250-5p is a novel tumor suppressive intronic miRNA co-regulated and silenced by promoter DNA methylation of its host gene AATK in NHL. MAPK1 and WDR1 are novel miR-1250-5p direct targets rendering inhibition of MAPK/ERK signaling and SDF-1-dependent cell migration, hence implicated in survival and dissemination of lymphoma.

Käesoleva artikli eesmärgiks on analüüsida, kuidas tehnoloogilised kuvandid sobituvad modernsuse perioodi laiemasse soolistatud kriisidiskursusesse. Palju on kirjutatud modernsusega seotud tajukriisist ja selle seotusest tehnoloogiaga, kuid vähem on uuritud seda, kuidas tajukriisi saab sobitada samal ajal domineerinud tajutud soolise kriisiga, eelkõige mehelikkuse kriisiga. Kuna paljud modernsuse kehalised, tajumuslikud ja esteetilised otsingud olid soolistatud, siis on viljakas küsida, kuidas soolistas modernism masinat ning kuidas mängisid selle soolistatud masinavärgiga modernsed naisautorid. Naisautoritele oli meesautoritest olulisem – või ka paratamatum – kirjutamine kehast lähtuvalt või kehast distantseerudes ning masinaesteetika on neile mitmest perspektiivist atraktiivne võimalus kirjutamise käigus vabaneda naistele omistatavast kehalisest ja immanentsest bioloogilisest paratamatusest. Käesolevas artiklis kasutatakse kirjandusnäiteid futurismi ja dadaismiga seotud inglise-ameerika naisluuletajalt Mina Loylt, kuid eesmärgiks pole niivõrd tema tekstide lähilugemine kui laiem arutelu masinaloogika ja soodiskursuste ristumise üle modernismi kontekstis. The present article sets out to explore how technological imagery interacts with the gendered crisis discourses prevalent in the period of modernity. Much has been written about the crises of perception and their associations with technology, but much less attention has been given to how they intersect with the perceived gender crisis, especially the crisis of masculinity dominant at the time. On the one hand, modernity celebrated the machine and sought to make male bodies into machines. Henry Ford was one of the lauded gods of the era and bodybuilding seemed to offer a way of treating the human body as a similar, sleek and controlled machine. On the other hand, although technology was engendered by male-centered society, it also seemed to be eating its sons, as it eroded male autonomy and rendered him into a mere cog in the machine. This creates a contradictory set of gendered images in which modernity is frequently associated with emasculation, especially when we consider the fact that the period also saw the assertive entry of women onto the public arena, as voters, creators and also consumers. The often openly violent radicalism of the new women posed a challenge to the male modernists who were seeking to achieve a revolution in perception but whose pursuits were confined to the pages of literary magazines. This creates a love-hate relationship between Anglo-American male modernists and feminism, as has been previously demonstrated by Marianne DeKoeven, Rachel Blau DuPlessis, and others. One way of resolving this tension is by rendering the woman machine-sleek, yet non-threatening, a technologically updated cyborg to fit the modern Pygmalion. This cyborg, as texts such as Fritz Lang’s Metropolis show, was nevertheless unsettling in its potential uncontrollability. It is this gendered ambivalence that the present article focuses on to ask whether the woman is just a cog in the wheel of modernism or whether she can also act as a spanner in the system. Specifically, the article asks how modernity gendered the machine and how women writers manipulated this gendered machine imagery. Women more than men had to write through or against the body and thus machine aesthetic was attractive to them as a means of writing themselves free from the bodily immanence traditionally attributed to women. The article builds on the work of Tim Armstrong (1998), Sara Danius (2002), Amelia Jones (2004), and Alex Goody (2007). The examples have been borrowed from the work of Anglo-American poet Mina Loy, but the aim is not a close reading of her literary texts, but the discussion of the intersection of machine logic and gender discourses in the context of modernism and modernity more broadly. Loy is placed into the Dadaist milieu where gender play was a widespread artistic tool for male and female artists (Marchel Duchamp, but also the much more marginal Elsa von Freytag-Lohringhoven). Loy, a major minor writer, was broadly celebrated in her day as an embodiment of modernity, somebody whose life was as important as her writing. Forgotten for decades, Loy has emerged again in literary scholarship owing to her frank representation of female body and sexuality. The present article, however, is less interested in her engagement with embodiment, but rather tackles her struggle in the field of tension between the impersonal aesthetics of high modernism and the need to write female subjectivity. This is where the use of machine imagery offers a creative solution. However, Loy’s machines do not copy those of Marinetti and other futurists whom Loy openly satirizes in her writing. She does not make the human body a machine prosthetic. Loy’s machines are organic, vulnerable and leaky. The article concludes that while male avant-garde writers projected their fear of the machine to the female body, the women writers are able to render the machine that does not work into a subversive critique of techno-reality that is defined from a narrowly male-centered perspective. This critique is the more subversive because it is presented in the impersonal language of male-centered high modernism. The woman modernist is both an ally and an enemy: she is mechanized as a part of the new technological culture but her physical body, with its leakiness and porousness, also breaks the rigid boundaries of machine aesthetics and perhaps also binary modes of perception.

In July 2001, New York couple Jason Black and Francis Schroeder opened bidding on the internet for corporate sponsorship of their newborn son. Naming rights started at $US5000 000. For Black, the logic was simple: given the inescapable prevalence of commercial sponsorship in contemporary life, this was a valid way of working with corporate America. Black and Schroeder already had two daughters and lived in a small two-bedroom apartment. In exchange for their son’s financial security, they risked branding him ‘Big Mac’ or ‘Nike’ – literally. If nothing else, the case exemplified the amazing reach of brand consciousness. The couple had internalised its values and rationale with such ease and comfort, the notion of forfeiting their child’s name was not abhorrent, but a lucrative marketing opportunity. Then again, the story was not without precedent. In 2000, teenagers Chris Barrett and Luke McCabe, both from New Jersey, became ‘spokesguys’ for First USA, one of America’s top credit-card companies. By sporting the company logo on their surfboards and all their clothes, the pair receives an annual $US40 000 each in tuition, board and books for their four-year university contract. They do not just advertise the brand; they are its living embodiment. For critics of consumer culture, such stories exemplify the extent to which corporatism has become a complete and closed system, with the panoramic presence of brands and logos and the commodification of life itself. They demonstrate the alarming readiness of some people to encode and enact the consumerist impulse. At its most malignant, this impulse appears as a crass consumerism that eats up every aspect of a culture, so much so that consumerism becomes the culture – all meaning is both anchored in and governed by the capitalist creed. For many, mass-produced contemporary culture provides a seemingly empty substitute, what Fredric Jameson (1991) termed “a new kind of flatness or depthlessness, a new kind of superficiality in the most literal sense” (9), for genuine experience and emotion. In turn, the contemporary consumer has been reduced to a mere imitation of mediated expectations, a functionary cog in the corporatist machine. As this sign system infects and invades more and more space, a certain cultural literacy is inevitably called for, an intimate knowledge of symbol and significance, logo and logic. However, like all living language, this one is open to some resistance, albeit a somewhat piecemeal one. Part appropriation, part antithesis, it is a resistance that hijacks form in order to subvert content. To explain how this type of activism might work, one could consider the highly effective activist operation, ®TMark (http://rtmark.com). ®TMark is an online centre that organizes and directs funding for the ‘information alteration’ of corporate products (otherwise known as ‘sabotage’). In 1993, ®TMark was involved in its first high-profile act of sabotage when it channelled $US 8000 to the Barbie Liberation Organization (BLO), a group that switched the voice boxes of 300 GI Joe and Barbie dolls. As befits a project affiliated with ®TMark, the critical content of BLO’s act was an alchemic stroke of humour and commentary. The protest lies within the ‘information alteration’ of commodities that usually rely on their supposed virtues. The BLO offensive drew attention to the questionable labour practices of Mattel, manufacturers of Barbie, thereby undermining the perceptions on which Barbie’s popularity rests. From the outset, ®TMark’s key feature is its corporate status. As a brokerage, ®TMark benefits from ‘limited liability’, just like any other corporation. It exploits this principle (that is, corporate protection, thereby bypassing legal responsibility) to sabotage other corporate products. Unlike other corporations, though, its bottom-line is cultural profit. As spokesperson Ray Thomas explains, the corporate model is both the object of ®TMark’s criticism, and the method by which that criticism is being facilitated: “Projects can be seen as stocks, and when you support a project you’re investing in it. When you contribute, say, $100 to a project that you would like to see accomplished, you are sort of investing in the accomplishment of the project. What you want to see out of that project is cultural dividends; you want to see a beneficial cultural event take place because of your money, as a reward. What you’re doing is investing in the improvement of the culture.” As with almost all ®TMark literature and material, the tone here is one of clipped civility, similar to the tense restraint characteristic of almost any corporation. Perhaps the closest the site gets to a ‘straightforward’ philosophy is in this piece of advice to dispirited students, fearful that, one day, they too will be sucked into the corporate void: “We believe that performing an ®TMark project can help you, psychologically at least, at such a difficult juncture; but more importantly, we urge you to at all costs remember that laws should defend human people, not corporate people like the one of which you will be a part. If you keep this in mind and work towards making it a reality, you may find your life much more bearable.” While this pseudo mission statement might be read as yet another appendage to ®TMark’s corporate veneer, it also points to some of the goals of the site. The depiction of ®TMark projects as morale boosters for disenchanted cynics goes some way in illustrating the ambitions and limits of the site. Rather than prescribe a far-reaching, holistic approach to social change (what might be termed a ‘revolutionary’ vision), ®TMark marshals ideas and initiatives a little more subtly. This is not to belittle or dispute its utility or significance; on the contrary, it is an approach that effectively (in)corporates a diverse range of people and programs. For example, rather than unifying its adherents to a common agenda, ®TMark operates as a coalition of interests. As such, the followings funds collectively serve the ®TMark project: the Labor Fund; the Frontier Fund (which challenges naïve visions of the ‘global village’); the Education Fund; the Health Fund; the Alternative Markets Fund (which considers overlooked demographics, such as poor gays); the Media Fund; the Intellectual Property Fund; the Biological Property Fund; the Corporate Law Fund; and the Environment Fund, among others. In turn, the ®TMark spectrum canvasses a plethora of pertinent, interconnected themes. This includes: the plight of workers in developing countries; censorship; institutionalised racism; the nominal triumph of consumer culture; techno-utopianism and the ‘digerati’; copyright law; and the increasing opacity of corporate activities. Underlying all these issues is ®TMark’s intention to publicise corporate abuses of democratic processes. Importantly, this multiplicity of interests is considered a suitable counterpart to the dispersed nature of corporate power. So, no one enemy is identified and targeted, since such reductionism belies the degree to which capitalism, corporatism and consumerism are irredeemably entwined in contemporary culture. In turn, these funds are often ‘managed’ by public figures whose association with certain causes lend their celebrity well to particular campaigns. For example, San Francisco band Negativeland manages the Intellectual Property Fund. This is most appropriate. Their 1991 legal battle with major label Island, on account of their ‘deceptive’ use of U2 material, cemented their place as champions of ‘creative appropriation’ and the right to create ‘with mirrors’ (as Negativeland describes it on their eponymous website). Similarly, the desire to create ‘with mirrors’ propels much of ®TMark’s work. It imbues all ®TMark projects with the same sense of calculated mischief. This suggests a mode of activism that is both opportunistic and ingenious, fashioning criticism from the very resources it is attacking. Financial reward aside (which, in any case, is negligible, at best) the real pay-off for ®TMark saboteurs comes via media coverage of their projects. As such, it straddles an interesting divide, between public infamy and necessary stealth. ®TMark requires media attention to render its projects effective, yet must maintain the critical distance necessary for any activist potency. Indeed, the need to bolster ®TMark’s profile was one of the reasons it went from being a dial-in system to a website in 1997. Within its first eight months the site had received almost 20 000 visits. In this schema, the activism in question is assigned a somewhat smaller purpose than has been hitherto associated with protest movements generally. Rather than provide a grand panacea for all the world’s ills, ®TMark’s scale is, by its own admission, modest: “The value of ®TMark is, and has always been, not in any real pressure it can possibly bear, but rather in its ability to quickly and cheaply attract widespread interest to important issues. ®TMark is thus essentially a public relations agency for anti-corporate activism”. In this way, ®TMark is firmly positioned within that strand of activism often referred to as ‘culture jamming’. This type of protest relies on a distinct degree of media and cultural literacy, one that is consonant with, and a product of, the Information Age. As Mark Dery explains, these activists “introduce noise into the signal as it passes from transmitter to receiver, encouraging idiosyncratic, unintended interpretations. Intruding on the intruders, they invest ads, newscasts, and other media artefacts with subversive meanings; simultaneously, they decrypt them, rendering their seductions impotent”(http://levity.com/markdery/culturejam.html). Culture jamming draws on (and contributes to) critiques of contemporary consumer capitalism. Its premise is that too much public space has already been ceded to Hollywood, Madison Avenue et al, and that activists must seize whatever opportunities allow this space to be reclaimed, however fleetingly. Trading on publicity and shock value, jammers manipulate those icons, slogans and trademarks that will register immediate recognition, thereby rendering their efforts meaningful. It constitutes a politicised refusal to submit to the cheerful passivity scripted by the corporate class. As jammers resist this role, reclaiming rather than forfeiting public space, they create what Naomi Klein (2000) calls “a climate of semiotic Robin Hoodism” (280). This term aptly captures the spirit of moralistic idealism that is, almost inevitably, a part of the milieu. This is not to dismiss or deride the progressive agenda of most culture jammers; if anything, it is a positive endorsement of their activism, and a response to those that would deem the postmodern zeitgeist politically barren or overwhelmingly cynical. What it reveals, then, is a somewhat unexpected distribution of power, as expressions of criticism and opposition emerge at seemingly incongruous junctures. They are at once engaged and complicit, finding cracks in ‘the system’ (that is, corporate society) and co-opting them, what Linda Hutcheon (1990) calls “subversion from within” (157). Eschewing ‘big picture’ solutions, culture jammers prioritise temporary connections and hybrid forms over ideological certainties and operational rigidity. Tactical thinking, and the malleability and mobility it relies on, clearly informs and animates ®TMark’s work. As Graham Meikle (2002) explains, “Different actions and campaigns use whichever media are most appropriate at any given time for any given purpose. An event might call for making a documentary, making a website, making an A4 newsletter, or making a phone call” (120). ®TMark stops short of overstating its purpose or exaggerating its success. There is no lofty manifesto or ironclad strategy; without departing too far from its anti-corporatist stance, ®TMark encourages an almost playful combination of comedy and critique, with a thick ironic overlay. At its most ambitious, then, ®TMark can hope to alter the everyday behaviour of ordinary citizens, making inroads at the expense of powerful corporations. At the very least, it can prompt bemused surfers to rethink certain things – such as Nike’s labour practices or Shell’s environmental record. In a sense, though, the degree to which such perceptual jolts can ‘make a difference’ is almost immaterial: the fact that the status quo has been questioned is a minor triumph. Where some commentators bemoan the virtual stupor they deem characteristic of contemporary Western politics, projects like ®TMark prove that there are spaces and opportunities left for meaningful debate and dissent. Works Cited Dery, Mark. “Culture Jamming: Hacking, Slashing and Sniping in the Empire of Signs”. (http://levity.com/markdery/culturejam.html). Hutcheon, Linda. The Politics of Postmodernity. London: Routledge, 1990. Jameson, Fredric. Postmodernism, or, The Cultural Logic of Late Capitalism. Durham: Duke University Press, 1991. Klein, Naomi. No Logo. London: Flamingo, 2000. Meikle, Graham. Future Active: Media Activism and the Internet. New York and London: Routledge, and Annandale, Pluto Press, 2002. Rtmark. (http://rtmark.com). Links http://levity.com/markdery/culturejam.html http://rtmark.com Citation reference for this article Substitute your date of access for Dn Month Year etc... MLA Style Khamis, Susie. "Jamming at Work " M/C: A Journal of Media and Culture< http://www.media-culture.org.au/0306/04-jamming.php>. APA Style Khamis, S. (2003, Jun 19). Jamming at Work . M/C: A Journal of Media and Culture, 6,< http://www.media-culture.org.au/0306/04-jamming.php>