Can We Exploit β-Lactamases Intrinsic Dynamics for Designing More Effective Inhibitors?

β-lactamases (BLs) represent the most frequent cause of antimicrobial resistance in Gram-negative bacteria. Despite the continuous efforts in the development of BL inhibitors (BLIs), new BLs able to hydrolyze the last developed antibiotics rapidly emerge. Moreover, the insurgence rate of effective mutations is far higher than the release of BLIs able to counteract them. This results in a shortage of antibiotics that is menacing the effective treating of infectious diseases. The situation is made even worse by the co-expression in bacteria of BLs with different mechanisms and hydrolysis spectra, and by the lack of inhibitors able to hit them all. Differently from other targets, BL flexibility has not been deeply exploited for drug design, possibly because of the small protein size, for their apparent rigidity and their high fold conservation. In this mini-review, we discuss the evidence for BL binding site dynamics being crucial for catalytic efficiency, mutation effect, and for the design of new inhibitors. Then, we report on identified allosteric sites in BLs and on possible allosteric inhibitors, as a strategy to overcome the frequent occurrence of mutations in BLs and the difficulty of competing efficaciously with substrates. Nevertheless, allosteric inhibitors could work synergistically with traditional inhibitors, increasing the chances of restoring bacterial susceptibility towards available antibiotics

Chimera: a Bioconductor package for secondary analysis of fusion products

Chimera is a Bioconductor package that organizes, annotates, analyses and validates fusions reported by different fusion detection tools; current implementation can deal with output from bellerophontes, chimeraScan, deFuse, fusionCatcher, FusionFinder, FusionHunter, FusionMap, mapSplice, Rsubread, tophat-fusion and STAR. The core of Chimera is a fusion data structure that can store fusion events detected with any of the aforementioned tools. Fusions are then easily manipulated with standard R functions or through the set of functionalities specifically developed in Chimera with the aim of supporting the user in managing fusions and discriminating falsepositive results

Architects of time: Labouring on digital futures

Drawing on critical analyses of the internet inspired by Gilles Deleuze and the Marxist autonomia movement, this paper suggests a way of understanding the impact of the internet and digital culture on identity and social forms through a consideration of the relationship between controls exercised through the internet, new subjectivities constituted through its use and new labour practices enabled by it. Following Castells, we can see that the distinction between user, consumer and producer is becoming blurred and free labour is being provided by users to corporations. The relationship between digital technologies and sense of community, through their relationship to the future, is considered for its dangers and potentials. It is proposed that the internet may be a useful tool for highlighting and enabling social connections if certain dangers can be traversed. Notably, current remedies for the lack of trust on the internet are questioned with an alternative, drawing on Zygmunt Bauman and Georg Simmel, proposed which is built on community through a vision of a ‘shared network’

A generator of peroxynitrite activatable with red light

The generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) as “unconventional” therapeutics with precise spatiotemporal control by using light stimuli may open entirely new horizons for innovative therapeutic modalities. Among ROS and RNS, peroxynitrite (ONOO(−)) plays a dominant role in chemistry and biology in view of its potent oxidizing power and cytotoxic action. We have designed and synthesized a molecular hybrid based on benzophenothiazine as a red light-harvesting antenna joined to an N-nitroso appendage through a flexible spacer. Single photon red light excitation of this molecular construct triggers the release of nitric oxide (˙NO) and simultaneously produces superoxide anions (O(2)˙(−)). The diffusion-controlled reaction between these two radical species generates ONOO(−), as confirmed by the use of fluorescein-boronate as a highly selective chemical probe. Besides, the red fluorescence of the hybrid allows its tracking in different types of cancer cells where it is well-tolerated in the dark but induces remarkable cell mortality under irradiation with red light in a very low concentration range, with very low light doses (ca. 1 J cm(−2)). This ONOO(−) generator activatable by highly biocompatible and tissue penetrating single photon red light can open up intriguing prospects in biomedical research, where precise and spatiotemporally controlled concentrations of ONOO(−) are required

Pulmonary function and CT scan imaging at low-level occupational exposureto asbestos

Background: In spite of the reduced exposure level, and its ban in numerous countries, compensation claims for asbestos-related diseases are far from decreasing. Methods: We used retrospective exposure assessment techniques to explore respiratory function and a computerized tomography (CT) scan in relation to past asbestos exposure in 115 male workers retired from an acrylic and polyester fiber plant. Based, on detailed information on exposure circumstances, we reconstructed a cumulative exposure estimate for each patient. Results: Time-weighted average exposure in our study population was 0.24 fibers/ml (95% confidence inteval (CI) 0.19–0.29), and the average cumulative exposure was 4.51 fibers/mL-years (95% CI 3.95–5.07). Exposure was elevated among maintenance workers, compared to other jobs (p = 0.00001). Respiratory function parameters did not vary in relation to the exposure estimates, nor to CT scan results. Risk of interstitial fibrosis showed a significant upward trend (Wald test for trend = 2.62, p = 0.009) with cumulative exposure to asbestos; risk associated with 5.26 fibers/mL-years or more, was 8-fold (95% CI 1.18–54.5). Conclusions: Our results suggest that a CT scan can detect pleuro-parenchymal lung alterations at asbestos exposure levels lower than previously thought, in absence of respiratory impairment. Further studies are required to validate our techniques of retrospective assessment of asbestos exposure

Game Workers and the Empire: Unionisation in the UK Video Game Industry

This article investigates some of the key debates that have emerged within the nascent union organising project Game Workers Unite, with a specific focus on its UK branch (GWU UK). The analysis is based on a period of participatory observation and a series of interviews with board members of GWU UK. This article evaluates Game Workers Unite (GWU) in relation to other recent attempts at unionising the game industry. It concludes that the strategies adopted to counter the hyper-visibility and individualisation of the game worker are key contributions of GWU in contemporary video game labour. This article draws on the work of Dyer-Witheford and de Peuter (2009) Games of empire: Global capitalism and video games to evaluate the historical specificity of GWU and the importance of the organisation for the contemporary video game industry

Anti-Equivalence: Pragmatics of post-liberal dispute

In the early 21st century, liberal democracies have witnessed their foundational norms of critique and deliberation being disrupted by a combination of populist and technological forces. A distinctive style of dispute has appeared, in which a speaker denounces the unfairness of all liberal and institutional systems of equivalence, including the measures of law, economics and the various other ‘tests’ which convention scholars have deemed core to organisations. The article reviews how sociologists of critique have tended to treat critical capacities as oriented towards consensus, but then considers how technologies of real-time ‘control’ circumvent liberal critique altogether. In response, a different type of dispute emerges in the digital public sphere, which abandons equivalences in general, instead adopting a non-representational template of warfare. This style of post-liberal dispute is manifest in the rhetoric of populists, but does not originate there