Chemotherapeutic compounds targeting the DNA double-strand break repair pathways : the good, the bad, and the promising

The repair of DNA double-strand breaks (DSBs) is a critical cellular mechanism that exists to ensure genomic stability. DNA DSBs are the most deleterious type of insult to a cell’s genetic material and can lead to genomic instability, apoptosis, or senescence. Incorrectly repaired DNA DSBs have the potential to produce chromosomal translocations and genomic instability, potentially leading to cancer. The prevalence of DNA DSBs in cancer due to unregulated growth and errors in repair opens up a potential therapeutic window in the treatment of cancers. The cellular response to DNA DSBs is comprised of two pathways to ensure DNA breaks are repaired: homologous recombination and non-homologous end joining. Identifying chemotherapeutic compounds targeting proteins involved in these DNA repair pathways has shown promise as a cancer therapy for patients, either as a monotherapy or in combination with genotoxic drugs. From the beginning, there have been a number of chemotherapeutic compounds that have yielded successful responses in the clinic, a number that have failed (CGK-733 and iniparib), and a number of promising targets for future studies identified. This review looks in detail at how the cell responds to these DNA DSBs and investigates the chemotherapeutic avenues that have been and are currently being explored to target this repair process.

Firm-customer mobile digital connectedness : conceptualization, measurement and implications

Firm-customer digital connectedness for effective sensing and responding is a strategic imperative for contemporary competitive firms. This research-in-progress paper conceptualizes and operationalizes the firm-customer mobile digital connectedness of a smart-mobile customer. The empirical investigation focuses on mobile app users and the impact of mobile apps on customer expectations. Based on pilot data collected from 127 customers, we tested hypotheses pertaining to firm-customer mobile digital connectedness and customer expectations. Our test analysis using linear and non-linear postulations reveals those customers raise their expectations as they increase their digital interactions with a firm.

Senataxin plays an essential role with DNA damage response proteins in meiotic recombination and gene silencing

Senataxin, mutated in the human genetic disorder ataxia with oculomotor apraxia type 2 (AOA2), plays an important role in maintaining genome integrity by coordination of transcription, DNA replication, and the DNA damage response. We demonstrate that senataxin is essential for spermatogenesis and that it functions at two stages in meiosis during crossing-over in homologous recombination and in meiotic sex chromosome inactivation (MSCI). Disruption of the Setx gene caused persistence of DNA double-strand breaks, a defect in disassembly of Rad51 filaments, accumulation of DNA:RNA hybrids (R-loops), and ultimately a failure of crossing-over. Senataxin localised to the XY body in a Brca1-dependent manner, and in its absence there was incomplete localisation of DNA damage response proteins to the XY chromosomes and ATR was retained on the axial elements of these chromosomes, failing to diffuse out into chromatin. Furthermore persistence of RNA polymerase II activity, altered ubH2A distribution, and abnormal XY-linked gene expression in Setx⁻/⁻ revealed an essential role for senataxin in MSCI. These data support key roles for senataxin in coordinating meiotic crossing-over with transcription and in gene silencing to protect the integrity of the genome.

Design guidelines for a mobile app for wellbeing of emerging adults

Mental health of young people may be improved through the use of mental health mobile applications,because young people engage with this technology freely. Mental health of young people is improved through the application of positive psychology, studies of which show that regular practice of one’s signature strength increases happiness and wellbeing, while decreasing depression. The issue is how to develop a mobile application intervention so that regular practice of one’s signature strength in novel ways occurs. This research project seeks to develop design guidelines discovered through the application of design thinking, actively working with emerging adults. In addition, this research is framed by the Design Science Research methodology to ensure that the resultant application is relevant and tested rigorously. This paper discusses the theory behind the application and discusses the research methods and research design, and will share the preliminary findings of the discovered design principles.

Global reconfiguration of a team of networked mobile robots among obstacles

This paper presents a full system demonstration of dynamic sensorbased reconfiguration of a networked robot team. Robots sense obstacles in their environment locally and dynamically adapt their global geometric configuration to conform to an abstract goal shape. We present a novel two-layer planning and control algorithm for team reconfiguration that is decentralised and assumes local (neighbour-to-neighbour) communication only. The approach is designed to be resource-efficient and we show experiments using a team of nine mobile robots with modest computation, communication, and sensing. The robots use acoustic beacons for localisation and can sense obstacles in their local neighbourhood using IR sensors. Our results demonstrate globally-specified reconfiguration from local information in a real robot network, and highlight limitations of standard mesh networks in implementing decentralised algorithms.

Enhanced fast handover triggering mechanism for fast proxy mobile IPv6

Handover performance is critical to support real-time traffic applications in wireless network communications. The longer the handover delay is, the longer an Mobile Node (MN) is prevented from sending and receiving any data packet. In real-time network communication applications, such as VoIP and video-conference, a long handover delay is often unacceptable. In order to achieve better handover performance, Fast Proxy Mobile IPv6 (FPMIPv6) has been standardised as an improvement to the original Proxy Mobile IPv6 (PMIPv6) in the Internet Engineering Task Force (IETF). The FPMIPv6 adopts a link layer triggering mechanism to perform two modes of operation: predictive and reactive modes. Using the link layer triggering, the handover performance of the FPMIPv6 can be improved in the predictive mode. However, an unsuccessful predictive handover operation will lead to activation of a reactive handover. In the reactive mode, MNs still experience long handover delays and a large amount of packet loss, which significantly degrade the handover performance of the FPMIPv6. Addressing this problem, this thesis presents an Enhanced Triggering Mechanism (ETM) in the FPMIPv6 to form an enhanced FPMIPv6 (eFPMIPv6). The ETM reduces the most time consuming processes in the reactive handover: the failed Handover Initiate (HO-Initiate) delay and bidirectional tunnel establishment delay. Consequently, the overall handover performance of the FPMIPv6 is enhanced in the eFPMIPv6. To show the advantages of the proposed eFPMIPv6, a theoretical analysis is carried out to mathematically model the performance of PMIPv6, FPMIPv6 and eFPMIPv6. Extensive case studies are conducted to validate the effectiveness of the presented eFPMIPv6 mechanism. They are carried out under various scenarios with changes in network link delay, traffic load, number of hops and MN moving velocity. The case studies show that the proposed mechanism ETM reduces the reactive handover delay, and the presented eFPMIPv6 outperforms the PMIPv6 and FPMIPv6 in terms of the overall handover performance.

Offspring of mothers fed a high fat diet display hepatic cell cycle inhibition and associated changes in gene expression and DNA methylation

The association between an adverse early life environment and increased susceptibility to later-life metabolic disorders such as obesity, type 2 diabetes and cardiovascular disease is described by the developmental origins of health and disease hypothesis. Employing a rat model of maternal high fat (MHF) nutrition, we recently reported that offspring born to MHF mothers are small at birth and develop a postnatal phenotype that closely resembles that of the human metabolic syndrome. Livers of offspring born to MHF mothers also display a fatty phenotype reflecting hepatic steatosis and characteristics of non-alcoholic fatty liver disease. In the present study we hypothesised that a MHF diet leads to altered regulation of liver development in offspring; a derangement that may be detectable during early postnatal life. Livers were collected at postnatal days 2 (P2) and 27 (P27) from male offspring of control and MHF mothers (n = 8 per group). Cell cycle dynamics, measured by flow cytometry, revealed significant G0/G1 arrest in the livers of P2 offspring born to MHF mothers, associated with an increased expression of the hepatic cell cycle inhibitor Cdkn1a. In P2 livers, Cdkn1a was hypomethylated at specific CpG dinucleotides and first exon in offspring of MHF mothers and was shown to correlate with a demonstrable increase in mRNA expression levels. These modifications at P2 preceded observable reductions in liver weight and liver:brain weight ratio at P27, but there were no persistent changes in cell cycle dynamics or DNA methylation in MHF offspring at this time. Since Cdkn1a up-regulation has been associated with hepatocyte growth in pathologic states, our data may be suggestive of early hepatic dysfunction in neonates born to high fat fed mothers. It is likely that these offspring are predisposed to long-term hepatic dysfunction.

An adaptive appearance-based map for long-term topological localization of mobile robots

"This work considers a mobile service robot which uses an appearance-based representation of its workplace as a map, where the current view and the map are used to estimate the current position in the environment. Due to the nature of real-world environments such as houses and offices, where the appearance keeps changing, the internal representation may become out of date after some time. To solve this problem the robot needs to be able to adapt its internal representation continually to the changes in the environment. This paper presents a method for creating an adaptive map for long-term appearance-based localization of a mobile robot using long-term and short-term memory concepts, with omni-directional vision as the external sensor."--publisher website

Toward an object-based semantic memory for long-term operation of mobile service robots

Throughout a lifetime of operation, a mobile service robot needs to acquire, store and update its knowledge of a working environment. This includes the ability to identify and track objects in different places, as well as using this information for interaction with humans. This paper introduces a long-term updating mechanism, inspired by the modal model of human memory, to enable a mobile robot to maintain its knowledge of a changing environment. The memory model is integrated with a hybrid map that represents the global topology and local geometry of the environment, as well as the respective 3D location of objects. We aim to enable the robot to use this knowledge to help humans by suggesting the most likely locations of specific objects in its map. An experiment using omni-directional vision demonstrates the ability to track the movements of several objects in a dynamic environment over an extended period of time.

Integrated analysis of epigenomic and genomic changes by DNA methylation dependent mechanisms provides potential novel biomarkers for prostate cancer

Epigenetic silencing mediated by CpG methylation is a common feature of many cancers. Characterizing aberrant DNA methylation changes associated with tumor progression may identify potential prognostic markers for prostate cancer (PCa). We treated two PCa cell lines, 22Rv1 and DU-145 with the demethylating agent 5-Aza 2’–deoxycitidine (DAC) and global methylation status was analyzed by performing methylation-sensitive restriction enzyme based differential methylation hybridization strategy followed by genome-wide CpG methylation array profiling. In addition, we examined gene expression changes using a custom microarray. Gene Set Enrichment Analysis (GSEA) identified the most significantly dysregulated pathways. In addition, we assessed methylation status of candidate genes that showed reduced CpG methylation and increased gene expression after DAC treatment, in Gleason score (GS) 8 vs. GS6 patients using three independent cohorts of patients; the publically available The Cancer Genome Atlas (TCGA) dataset, and two separate patient cohorts. Our analysis, by integrating methylation and gene expression in PCa cell lines, combined with patient tumor data, identified novel potential biomarkers for PCa patients. These markers may help elucidate the pathogenesis of PCa and represent potential prognostic markers for PCa patients.

Secondary user relations in emerging mobile computing environments

Mobile technologies are enabling access to information in diverse environ.ments, and are exposing a wider group of individuals to said technology. Therefore, this paper proposes that a wider view of user relations than is usually considered in information systems research is required. Specifically, we examine the potential effects of emerging mobile technologies on end-­‐user relations with a focus on the ‘secondary user’, those who are not intended to interact directly with the technology but are intended consumers of the technology’s output. For illustration, we draw on a study of a U.K. regional Fire and Rescue Service and deconstruct mobile technology use at Fire Service incidents. Our findings provide insights, which suggest that, because of the nature of mobile technologies and their context of use, secondary user relations in such emerging mobile environments are important and need further exploration.

Efficiently capturing large, complex cultural heritage sites with a handheld mobile 3D laser mapping system

Accurate three-dimensional representations of cultural heritage sites are highly valuable for scientific study, conservation, and educational purposes. In addition to their use for archival purposes, 3D models enable efficient and precise measurement of relevant natural and architectural features. Many cultural heritage sites are large and complex, consisting of multiple structures spatially distributed over tens of thousands of square metres. The process of effectively digitising such geometrically complex locations requires measurements to be acquired from a variety of viewpoints. While several technologies exist for capturing the 3D structure of objects and environments, none are ideally suited to complex, large-scale sites, mainly due to their limited coverage or acquisition efficiency. We explore the use of a recently developed handheld mobile mapping system called Zebedee in cultural heritage applications. The Zebedee system is capable of efficiently mapping an environment in three dimensions by continually acquiring data as an operator holding the device traverses through the site. The system was deployed at the former Peel Island Lazaret, a culturally significant site in Queensland, Australia, consisting of dozens of buildings of various sizes spread across an area of approximately 400 × 250 m. With the Zebedee system, the site was scanned in half a day, and a detailed 3D point cloud model (with over 520 million points) was generated from the 3.6 hours of acquired data in 2.6 hours. We present results demonstrating that Zebedee was able to accurately capture both site context and building detail comparable in accuracy to manual measurement techniques, and at a greatly increased level of efficiency and scope. The scan allowed us to record derelict buildings that previously could not be measured because of the scale and complexity of the site. The resulting 3D model captures both interior and exterior features of buildings, including structure, materials, and the contents of rooms.

Food talks back : Exploring the role of mobile applications in reducing domestic food wastage

Mitigating domestic food waste reduces its environmental and economic impacts. In our study, we have identified the use of mobile technology to support behaviour change as a key tool to assist the process of reducing food waste. This paper reports on three mobile applications designed to reduce domestic food waste: Fridge Pal, LeftoverSwap and EatChaFood. The paper examines how each app can influence consumer knowledge of domestic food supply, location, and literacy. We discuss our findings with respect to three considerations: (i) assisting with the user’s food supply and location knowledge; (ii) improving the user’s food literacy; (iii) facilitating social food sharing of excess food. We present new insights for mobile interventions that encourage changes towards more sustainable behaviours to reduce food waste.

The impact of mobile phone distraction on the braking behaviour of young drivers : a hazard-based duration model

Braking is a crucial driving task with a direct relationship with crash risk, as both excess and inadequate braking can lead to collisions. The objective of this study was to compare the braking profile of young drivers distracted by mobile phone conversations to non-distracted braking. In particular, the braking behaviour of drivers in response to a pedestrian entering a zebra crossing was examined using the CARRS-Q Advanced Driving Simulator. Thirty-two licensed drivers drove the simulator in three phone conditions: baseline (no phone conversation), hands-free, and handheld. In addition to driving the simulator, each participant completed questionnaires related to driver demographics, driving history, usage of mobile phones while driving, and general mobile phone usage history. The drivers were 18–26 years old and split evenly by gender. A linear mixed model analysis of braking profiles along the roadway before the pedestrian crossing revealed comparatively increased decelerations among distracted drivers, particularly during the initial 20 kph of deceleration. Drivers’ initial 20 kph deceleration time was modelled using a parametric accelerated failure time (AFT) hazard-based duration model with a Weibull distribution with clustered heterogeneity to account for the repeated measures experiment design. Factors found to significantly influence the braking task included vehicle dynamics variables like initial speed and maximum deceleration, phone condition, and driver-specific variables such as licence type, crash involvement history, and self-reported experience of using a mobile phone whilst driving. Distracted drivers on average appear to reduce the speed of their vehicle faster and more abruptly than non-distracted drivers, exhibiting excess braking comparatively and revealing perhaps risk compensation. The braking appears to be more aggressive for distracted drivers with provisional licenses compared to drivers with open licenses. Abrupt or excessive braking by distracted drivers might pose significant safety concerns to following vehicles in a traffic stream.