Insults, free speech and offensiveness

This article examines what is wrong with some expressive acts, ‘insults’. Their putative wrongfulness is distinguished from the causing of indirect harms, aggregated harms, contextual harms, and damaging misrepresentations. The article clarifies what insults are, making use of work by Neu and Austin, and argues that their wrongfulness cannot lie in the hurt that is caused to those at whom such acts are directed. Rather it must lie in what they seek to do, namely to denigrate the other. The causing of offence is at most evidence that an insult has been communicated; it is not independent grounds of proscription or constraint. The victim of an insult may know that she has been insulted but not accept or agree with the insult, and thereby submit to the insulter. Hence insults need not, as Waldron argues they do, occasion dignitary harms. They do not of themselves subvert their victims' equal moral status. The claim that hateful speech endorses inequality should not be conflated with a claim that such speech directly subverts equality.

Thus, ‘wounding words’ should not unduly trouble the liberal defender of free speech either on the grounds of preventing offence or on those of avoiding dignitary harms.

The interleukin 1beta gene promoter polymorphism (-511) acts as a risk factor for psychosis in Alzheimer's dementia

The explanation for why some patients develop psychotic change in Alzheimer's disease (AD) is unclear. "Psychosis-modifier genes" may act in the setting of neurodegeneration to produce AD plus psychosis in a similar way to how genetic modulation during neurodevelopment leads to schizophrenia. Because there is increasing interest in the common disruption of cytokine pathways seen in both AD and schizophrenia, we tested the association between the functional interleukin-1beta -511 promoter polymorphism with delusions and hallucinations in AD. Significant associations between psychotic symptoms and the CC genotype (p = 0.001 - p = 0.043) and C allele (p = 0.014 vs p = 0.048) were found, thus confirming the previously noted increased risk in schizophrenia.

ATM acts downstream of ATR in the DNA damage response signaling of bystander cells.

This study identifies ataxia-telangiectasia mutated (ATM) as a further component of the complex signaling network of radiation-induced DNA damage in nontargeted bystander cells downstream of ataxia-telangiectasia and Rad3-related (ATR) and provides a rationale for molecular targeted modulation of these effects. In directly irradiated cells, ATR, ATM, and DNA-dependent protein kinase (DNA-PK) deficiency resulted in reduced cell survival as predicted by the known important role of these proteins in sensing DNA damage. A decrease in clonogenic survival was also observed in ATR/ATM/DNA-PK–proficient, nonirradiated bystander cells, but this effect was completely abrogated in ATR and ATM but not DNA-PK–deficient bystander cells. ATM activation in bystander cells was found to be dependent on ATR function. Furthermore, the induction and colocalization of ATR, 53BP1, ATM-S1981P, p21, and BRCA1 foci in nontargeted cells was shown, suggesting their involvement in bystander DNA damage signaling and providing additional potential targets for its modulation. 53BP1 bystander foci were induced in an ATR-dependent manner predominantly in S-phase cells, similar to ?H2AX foci induction. In conclusion, these results provide a rationale for the differential modulation of targeted and nontargeted effects of radiation.

Professing translation: the acts-in-between

Drawing on scholarship in translation ethics (Berman 1992; Cronin 2003) and performance studies (Conquergood 2002; Jackson 2004), this article approaches translation in the theatre from the double perspective of theory and practice. Professing translation as a model for the resolution of entrenched binaries (scholar/artist; theoretician/practitioner), the author sees the practice of translating for performance not just as a method of discovery or a hermeneutic tool but also as a mode of reflection that brings together both “readerly” and “writerly” approaches to text (Barthes 1974). By drawing on the experience of writing translations of García Lorca for the Belgrade Theatre, Calderón for the Royal Shakespeare Company, and Lope de Vega for the Watermill Theatre and the Washington Shakespeare Theatre, the article attempts to characterise such translation as an act of physical imagination, of a holistic understanding of both language and performance, into which textuality is incorporated and by which it is superseded. © John Benjamins Publishing Company

Impure Thinking Practices and Clinical Acts: The Sonorous Becomings of Heidi Fast

This article introduces the recent sound works of Heidi Fast, a Finnish voice and performance artist. Fast’s creative practice operates between art and philosophy, and articulates several ‘zones of becoming’: what Fast designates as ‘the clinical’, ‘the virtual’ and ‘vocal thought-material’. Using a methodology of routing, the article shows how these zones emerge as aesthetic, ethical and political concerns within Fast’s work. Since 2005, Fast’s sound works have variously taken shape as miniature concerts, social sculptures, imaginary soundscapes and environmental music performances. Drawing upon the writings of theorists who have helped shape her practice, this article argues that Fast uses sound and voice to propose an ‘actualising philosophy’. This philosophy actualises virtualities (unrealised potentials), affecting transformative shifts through tiny mutations in perceptions and behaviours.

The lipopolysaccharide core of Brucella abortus acts as a shield against innate immunity recognition

Innate immunity recognizes bacterial molecules bearing pathogen-associated molecular patterns to launch inflammatory responses leading to the activation of adaptive immunity. However, the lipopolysaccharide (LPS) of the gram-negative bacterium Brucella lacks a marked pathogen-associated molecular pattern, and it has been postulated that this delays the development of immunity, creating a gap that is critical for the bacterium to reach the intracellular replicative niche. We found that a B. abortus mutant in the wadC gene displayed a disrupted LPS core while keeping both the LPS O-polysaccharide and lipid A. In mice, the wadC mutant induced proinflammatory responses and was attenuated. In addition, it was sensitive to killing by non-immune serum and bactericidal peptides and did not multiply in dendritic cells being targeted to lysosomal compartments. In contrast to wild type B. abortus, the wadC mutant induced dendritic cell maturation and secretion of pro-inflammatory cytokines. All these properties were reproduced by the wadC mutant purified LPS in a TLR4-dependent manner. Moreover, the core-mutated LPS displayed an increased binding to MD-2, the TLR4 co-receptor leading to subsequent increase in intracellular signaling. Here we show that Brucella escapes recognition in early stages of infection by expressing a shield against recognition by innate immunity in its LPS core and identify a novel virulence mechanism in intracellular pathogenic gram-negative bacteria. These results also encourage for an improvement in the generation of novel bacterial vaccines.

RUNX3 acts as a tumor suppressor in breast cancer by targeting estrogen receptor α

Transcription factor RUNX3 is inactivated in a number of malignancies, including breast cancer, and is suggested to function as a tumor suppressor. How RUNX3 functions as a tumor suppressor in breast cancer remains undefined. Here, we show that about 20% of female Runx3(+/-) mice spontaneously developed ductal carcinoma at an average age of 14.5 months. Additionally, RUNX3 inhibits the estrogen-dependent proliferation and transformation potential of ERa-positive MCF-7 breast cancer cells in liquid culture and in soft agar and suppresses the tumorigenicity of MCF-7 cells in severe combined immunodeficiency mice. Furthermore, RUNX3 inhibits ERa-dependent transactivation by reducing the stability of ERa. Consistent with its ability to regulate the levels of ERa, expression of RUNX3 inversely correlates with the expression of ERa in breast cancer cell lines, human breast cancer tissues and Runx3(+/-) mouse mammary tumors. By destabilizing ERa, RUNX3 acts as a novel tumor suppressor in breast cancer.

A conserved spider silk domain acts as a molecular switch that controls fibre assembly

A huge variety of proteins are able to form fibrillar structures(1), especially at high protein concentrations. Hence, it is surprising that spider silk proteins can be stored in a soluble form at high concentrations and transformed into extremely stable fibres on demand(2,3). Silk proteins are reminiscent of amphiphilic block copolymers containing stretches of polyalanine and glycine-rich polar elements forming a repetitive core flanked by highly conserved non-repetitive amino-terminal(4,5) and carboxy-terminal(6) domains. The N-terminal domain comprises a secretion signal, but further functions remain unassigned. The C-terminal domain was implicated in the control of solubility and fibre formation(7) initiated by changes in ionic composition(8,9) and mechanical stimuli known to align the repetitive sequence elements and promote beta-sheet formation(10-14). However, despite recent structural data(15), little is known about this remarkable behaviour in molecular detail. Here we present the solution structure of the C-terminal domain of a spider dragline silk protein and provide evidence that the structural state of this domain is essential for controlled switching between the storage and assembly forms of silk proteins. In addition, the C-terminal domain also has a role in the alignment of secondary structural features formed by the repetitive elements in the backbone of spider silk proteins, which is known to be important for the mechanical properties of the fibre.