Have You Updated Your Toaster? Transatlantic Approaches to Governing the Internet of Everything

As Internet-connected devices become ubiquitous, it remains an open question whether security— or privacy—can or will scale, or whether a combination of perverse incentives, new problems, and new impacts of old problems like “technical debt” amassing from products being rushed to market before being fully vetted, will derail progress and exacerbate cyber insecurity. This Article investigates contemporary approaches to Internet of Things (IoT) governance through an in- depth comparative case study focusing on the European Union (EU) and the United States. Particular attention is paid to the impact on IoT security of the General Data Protection Regulation (GDPR) and the Network Information Security (NIS) Directive in the EU, and the influence of the U.S. National Institute for Standards and Technology Cybersecurity Framework (NIST CSF), with a focus on mitigating the risk of politically motivated attacks on civilians. We analyze reform proposals and apply lessons from major prior Internet governance debates to argue for a polycentric approach to improving IoT security and privacy in the transatlantic context

Perspective Access Networks

Perspective Access Networks provide an infrastructure from which users can specify the location from which they wish to view the Internet. The ability to specify location has become necessary as the Internet has become increasingly inconsistent. An increasing preponderance of middleboxes, location-dependent services, and large-scale content filtering have contributed to this situation. Our work offers the following contributions. First, we propose an infrastructure that routes traffic to a location from which a given resource can be viewed, taking instructions from user-specified attributes describing the desired location. Second, we analyze the tradeoff between the expressivity of user requests and the finite resources available within the network for propagating metadata about available perspectives. Third, we stipulate a set of real scenarios that fall within the limits of what can reasonably be handled by a system appropriately tuned to manage the tradeoff, and we argue that the specific algorithm we propose can handle the scenarios effectively.Engineering and Applied Science

Pojamide: An HDAC3-selective ferrocene analogue with remarkably enhanced redox-triggered ferrocenium activity in cells.

A ferrocene containing ortho-aminoanilide, N1-(2-aminophenyl)-N8-ferrocenyloctanediamide, 2b (Pojamide) displayed nanomolar potency vs. HDAC3. Compared to RGFP966, a potent and selective HDAC3 inhibitor, Pojamide displayed superior activity in HCT116 colorectal cancer cell invasion assays; however, TCH106 and Romidepsin, potent HDAC1 inhibitors, outperformed Pojamide in cellular proliferation and colony formation assays. Together, these data suggest that HDAC 1 & 3 inhibition is desirable to achieve maximum anti-cancer benefits. Additionally, we explored Pojamide-induced redox-pharmacology. Indeed, treating HCT116 cells with Pojamide, SNP (sodium nitroprusside) and glutathione (GSH) led to greatly enhanced cytotoxicity and DNA damage attributed to activation to an Fe(III) species

Transcription control by the ENL YEATS domain in acute leukaemia

Recurrent chromosomal translocations producing a chimaeric MLL oncogene give rise to a highly aggressive acute leukaemia associated with poor clinical outcome. The preferential involvement of chromatin-associated factors as MLL fusion partners belies a dependency on transcription control. Despite recent progress made in targeting chromatin regulators in cancer, available therapies for this well-characterized disease remain inadequate, prompting the need to identify new targets for therapeutic intervention. Here, using unbiased CRISPR-Cas9 technology to perform a genome-scale loss-of-function screen in an MLL-AF4-positive acute leukaemia cell line, we identify ENL as an unrecognized gene that is specifically required for proliferation in vitro and in vivo. To explain the mechanistic role of ENL in leukaemia pathogenesis and dynamic transcription control, a chemical genetic strategy was developed to achieve targeted protein degradation. Acute loss of ENL suppressed the initiation and elongation of RNA polymerase II at active genes genome-wide, with pronounced effects at genes featuring a disproportionate ENL load. Notably, an intact YEATS chromatin-reader domain was essential for ENL-dependent leukaemic growth. Overall, these findings identify a dependency factor in acute leukaemia and suggest a mechanistic rationale for disrupting the YEATS domain in disease.K. LubinE. Wood

Enhancer invasion shapes MYCN-dependent transcriptional amplification in neuroblastoma.

Amplification of the locus encoding the oncogenic transcription factor MYCN is a defining feature of high-risk neuroblastoma. Here we present the first dynamic chromatin and transcriptional landscape of MYCN perturbation in neuroblastoma. At oncogenic levels, MYCN associates with E-box binding motifs in an affinity-dependent manner, binding to strong canonical E-boxes at promoters and invading abundant weaker non-canonical E-boxes clustered at enhancers. Loss of MYCN leads to a global reduction in transcription, which is most pronounced at MYCN target genes with the greatest enhancer occupancy. These highly occupied MYCN target genes show tissue-specific expression and are linked to poor patient survival. The activity of genes with MYCN-occupied enhancers is dependent on the tissue-specific transcription factor TWIST1, which co-occupies enhancers with MYCN and is required for MYCN-dependent proliferation. These data implicate tissue-specific enhancers in defining often highly tumor-specific 'MYC target gene signatures' and identify disruption of the MYCN enhancer regulatory axis as a promising therapeutic strategy in neuroblastoma

Structure-Guided DOT1L Probe Optimization by Label-Free Ligand Displacement

The DOT1L lysine methyltransferase has emerged as a validated therapeutic target in MLL-rearranged (MLLr) acute leukemias. Although S-adenosylmethionine competitive inhibitors have demonstrated pharmacological proof-of-principle in MLLr-leukemia, these compounds require further optimization to improve cellular potency and pharmacokinetic stability. Limiting DOT1L inhibitor discovery and ligand optimization have been complex biochemical methods often using radionucleotides and cellular methods requiring prolonged culture. We therefore developed a new suite of assay technologies that allows comparative assessment of chemical tools for DOT1L in a miniaturized format. Coupling these assays with structural information, we developed new insights into DOT1L ligand binding and identified several functionalized probes with increased cellular potency (IC50 values ∼10 nM) and excellent selectivity for DOT1L. Together these assay technologies define a platform capability for discovery and optimization of small-molecule DOT1L inhibitors