Consequences of Cisplatin Binding on Nucleosome Structure and Dynamics

The effects of cisplatin binding to DNA were explored at the nucleosome level to incorporate key features of the eukaryotic nuclear environment. An X-ray crystal structure of a site-specifically platinated nucleosome carrying a 1,3-cis-{Pt(NH[subscript 3])[subscript 2]}[superscript 2+]-d(GpTpG) intrastrand cross-link reveals the details of how this adduct dictates the rotational positioning of DNA in the nucleosome. Results from in vitro nucleosome mobility assays indicate that a single platinum adduct interferes with ATP-independent sliding of DNA around the octamer core. Data from in vitro transcription experiments suggest that RNA polymerases can successfully navigate along cisplatin-damaged DNA templates that contain nucleosomes, but stall when the transcription elongation complex physically contacts a platinum cross-link located on the template strand. These results provide information about the effects of cisplatin binding to nuclear DNA and enhance our understanding of the mechanism of transcription inhibition by platinum anticancer compounds.National Cancer Institute (U.S.) (Grant CA034992)David H. Koch Cancer Research FundNational Center for Research Resources (U.S.) (Award RR-15301)United States. Dept. of Energy. Office of Basic Energy Sciences (DE-AC02-06CH11357

Structure of duplex DNA containing the cisplatin 1,2-{Pt(NH3)2}2+-d(GpG) crosslink at 1.77 Å resolution

We report the 1.77-Å resolution X-ray crystal structure of a dodecamer DNA duplex with the sequence 5′-CCTCTGGTCTCC-3′ that has been modified to contain a single engineered 1,2-cis-{Pt(NH3)2}2+-d(GpG) cross-link, the major DNA adduct of cisplatin. These data represent a significant improvement in resolution over the previously published 2.6-Å structure. The ammine ligands in this structure are clearly resolved, leading to improved visualization of the cross-link geometry with respect to both the platinum center and to the nucleobases, which adopt a higher energy conformation. Also better resolved are the deoxyribose sugar puckers, which allow us to re-examine the global structure of platinum-modified DNA. Another new feature of this model is the location of four octahedral [Mg(H2O)6]2+ ions associated with bases in the DNA major groove and the identification of 124 ordered water molecules that participate in hydrogen-bonding interactions with either the nucleic acid or the diammineplatinum(II) moiety.National Cancer Institute (U.S.) (grant CA034992)David H. Koch Institute for Integrative Cancer Research at MIT (Koch Fund Fellowship

Bright Fluorescent Chemosensor Platforms for Imaging Endogenous Pools of Neuronal Zinc

AbstractA series of new fluorescent Zinpyr (ZP) chemosensors based on the fluorescein platform have been prepared and evaluated for imaging neuronal Zn2+. A systematic synthetic survey of electronegative substitution patterns on a homologous ZP scaffold provides a basis for tuning the fluorescence responses of “off-on” photoinduced electron transfer (PET) probes by controlling fluorophore pKa values and attendant proton-induced interfering fluorescence of the metal-free (apo) probes at physiological pH. We further establish the value of these improved optical tools for interrogating the metalloneurochemistry of Zn2+; the novel ZP3 fluorophore images endogenous stores of Zn2+ in live hippocampal neurons and slices, including the first fluorescence detection of Zn2+ in isolated dentate gyrus cultures. Our findings reveal that careful control of fluorophore pKa can minimize proton-induced fluorescence of the apo probes and that electronegative substitution offers a general strategy for tuning PET chemosensors for cellular studies. In addition to providing improved optical tools for Zn2+ in the neurosciences, these results afford a rational starting point for creating superior fluorescent probes for biological applications

Constellations of identity: place-ma(r)king beyond heritage

This paper will critically consider the different ways in which history and belonging have been treated in artworks situated in the Citadel development in Ayr on the West coast of Scotland. It will focus upon one artwork, Constellation by Stephen Hurrel, as an alternative to the more conventional landscapes of heritage which are adjacent, to examine the relationship between personal history and place history and argue the primacy of participatory process in the creation of place and any artwork therein. Through his artwork, Hurrel has attempted to adopt a material process through which place can be created performatively but, in part due to its non-representational form, proves problematic, aesthetically and longitudinally, in wholly engaging the community. The paper will suggest that through variants of ‘new genre public art’ such as this, personal and place histories can be actively re-created through the redevelopment of contemporary urban landscapes but also highlight the complexities and indeterminacies involved in the relationship between artwork, people and place

Eco-aesthetic dimensions: Herbert Marcuse, ecollogy and art

In his last book, The Aesthetic Dimension (1978), Marcuse argued that a concern for aesthetics is justified when political change is unlikely. But the relation between aesthetics and politics is oblique: “Art cannot change the world, but it can contribute to changing the consciousness … of the men and women who could change the world.” (p. 33). Marcuse also linked his critique of capitalism to environmentalism in the early 1970s: “the violation of the Earth is a vital aspect of the counterrevolution.” (Ecology and Revolution, in The New Left and the 1960s, Collected Papers 3, 2005, p. 173). This article revisits Marcuse’s ideas on aesthetics and ecology, and reviews two recent art projects which engage their audiences in ecological issues: The Jetty Project (2014) by Wolfgang Weileder—which used recycled material and community participation to construct a temporary monument within a wider conservation project on the Tyne, N-E England—and Fracking Futures by HeHe (Helen Evans and Heiko Hansen)—which turned the interior of the gallery at FACT, Liverpool, into what appeared to be a fracking site. The aim is not to evaluate the projects, nor to test the efficacy of Marcuse’s ideas, more to ask again whether art has a role in a shift of attitude which might contribute to dealing with the political and economic causes of climate change

Synergistic cytotoxicity of irinotecan and cisplatin in dual-drug targeted polymeric nanoparticles

Aim: Two unexplored aspects for irinotecan and cisplatin (I&C) combination chemotherapy are: actively targeting both drugs to a specific diseased cell type, and delivering both drugs on the same vehicle to ensure their synchronized entry into the cell at a well-defined ratio. In this work, the authors report the use of targeted polymeric nanoparticles (NPs) to coencapsulate and deliver I&C to cancer cells expressing the prostate-specific membrane antigen. Materials & methods: Targeted NPs were prepared in a single step by mixing four different precursors inside microfluidic devices. Results: I&C were encapsulated in 55-nm NPs and showed an eightfold increase in internalization by prostate-specific membrane antigen-expressing LNCaP cells compared with nontargeted NPs. NPs coencapsulating both drugs exhibited strong synergism in LNCaP cells with a combination index of 0.2. Conclusion: The strategy of coencapsulating both I&C in a single NP targeted to a specific cell type could potentially be used to treat different types of cancer.Prostate Cancer Foundation (Nanotherapeutics Award)MIT-Harvard Center of Cancer Nanotechnology Excellence (U54-CA151884)National Science Foundation (U.S.). Graduate Research Fellowship ProgramAmerican Society for Engineering Education. National Defense Science and Engineering Graduate Fellowshi

Lifeworld Inc. : and what to do about it

Can we detect changes in the way that the world turns up as they turn up? This paper makes such an attempt. The first part of the paper argues that a wide-ranging change is occurring in the ontological preconditions of Euro-American cultures, based in reworking what and how an event is produced. Driven by the security – entertainment complex, the aim is to mass produce phenomenological encounter: Lifeworld Inc as I call it. Swimming in a sea of data, such an aim requires the construction of just enough authenticity over and over again. In the second part of the paper, I go on to argue that this new world requires a different kind of social science, one that is experimental in its orientation—just as Lifeworld Inc is—but with a mission to provoke awareness in untoward ways in order to produce new means of association. Only thus, or so I argue, can social science add to the world we are now beginning to live in

Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug

Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Here we use single-cell imaging of intratumoral TNP pharmacokinetics and pharmacodynamics to better comprehend their heterogeneous behaviour. Model TNPs comprising a fluorescent platinum(IV) pro-drug and a clinically tested polymer platform (PLGA-b-PEG) promote long drug circulation and alter accumulation by directing cellular uptake toward tumour-associated macrophages (TAMs). Simultaneous imaging of TNP vehicle, its drug payload and single-cell DNA damage response reveals that TAMs serve as a local drug depot that accumulates significant vehicle from which DNA-damaging Pt payload gradually releases to neighbouring tumour cells. Correspondingly, TAM depletion reduces intratumoral TNP accumulation and efficacy. Thus, nanotherapeutics co-opt TAMs for drug delivery, which has implications for TNP design and for selecting patients into trials.National Cancer Institute (U.S.) (Grant RO1-CA034992