Role of Nucleotide Excision Repair in Cisplatin Resistance

Cisplatin is a chemotherapeutic drug used for the treatment of a number of cancers. The efficacy of cisplatin relies on its binding to DNA and the induction of cytotoxic DNA damage to kill cancer cells. Cisplatin-based therapy is best known for curing testicular cancer; however, treatment of other solid tumors with cisplatin has not been as successful. Pre-clinical and clinical studies have revealed nucleotide excision repair (NER) as a major resistance mechanism against cisplatin in tumor cells. NER is a versatile DNA repair system targeting a wide range of helix-distorting DNA damage. The NER pathway consists of multiple steps, including damage recognition, pre-incision complex assembly, dual incision, and repair synthesis. NER proteins can recognize cisplatin-induced DNA damage and remove the damage from the genome, thereby neutralizing the cytotoxicity of cisplatin and causing drug resistance. Here, we review the molecular mechanism by which NER repairs cisplatin damage, focusing on the recent development of genome-wide cisplatin damage mapping methods. We also discuss how the expression and somatic mutations of key NER genes affect the response of cancer cells to cisplatin. Finally, small molecules targeting NER factors provide important tools to manipulate NER capacity in cancer cells. The status of research on these inhibitors and their implications in cancer treatment will be discussed.     

Behaviour of persistent organochlorine micropollutants during primary sedimentation of waste water

The removal of polychlorinated biphenyls and the organochlorine insecticides gamma-HCH, aldrin, dieldrin and endrin during primary sedimentation of raw sewage has been studied using a pilot plant facility. A matrix of sixteen experiments was performed, where the pilot plant was operated at four different hydraulic loadings with four different influent suspended solids loadings. Significant removals of micropollutants into the primary sludge were observed, although no particular relationship with the removal of suspended solids was evident. It is concluded that a proportion of the organic microcontaminants present in raw sewage were associated with non-settleable solids and were also in the dissolved form. The significance of the behaviour of organochlorine micropollutants in waste water treatment processes and the hydrological cycle are discussed in the context of water re-use operations.     

Collection of daily patient reported outcomes is feasible and demonstrates differential patient experience in chronic kidney disease

Introduction: Patient reported outcomes (PROs) are a critical metric documenting the impact of disease and treatment from the patient's perspective. A variety of generic and disease specific PRO measures (PROMs) are used in chronic kidney disease (CKD) but studies are primarily cross‐sectional. None of the available PROMs are designed for frequent iterative application. Methods: An online PROM for daily use in dialysis and CKD 4/5 patients was developed. The custom website utilised visual analogue scales to capture 6 PROs (general well being (GWB), pain, sleep, breathing, energy, and appetite). Outcomes of interest were uptake, response rates, intermodality variation, and change in PRO corresponding to predefined events. Findings: Forty‐three patients submitted at least once and 34 submitted beyond 30 days. Median follow‐up was 247 days, 64% male, age 62 ± 12 years. In individuals submitting for >30 days, dialysis patients had significantly worse median scores compared to CKD for sleep (47[32–80], 97[76–99], P = 0.003), appetite (66[50–96], 97[88–100], P = 0.008), energy (47[40–89], 84[67–96], P = 0.031), and GWB (63[49–94], 93[71–98], P = 0.026). Patients demonstrated a variety of stable bandwidths of response, deviations from this were associated with specific events e.g., acute admission, vascular procedures, disturbed fluid status, and dialysis start. Discussion: We successfully introduced an online, patient acceptable, iterative PROM that discriminates symptom burden, cross‐sectionally, and longitudinally. Further work will prospectively examine the predictive power of changes in PRO and more rigorously investigate the potential use of these methods to optimise patient care.     

The effectiveness of Light Rail transit in achieving regional CO<Subscript>2</Subscript> emissions targets is linked to building energy use: insights from system dynamics modeling

Cities worldwide face the challenges of accommodating a growing population, while reducing emissions to meet climate mitigation targets. Public transit investments are often proposed as a way to curb emissions while maintaining healthy urban economies. However, cities face a system-level challenge in that transportation systems have cascading effects on land use and economic development. Understanding how an improved public transit system could affect urban growth and emissions requires a system-level view of a city, to anticipate side effects that could run counter to policy goals. To address this knowledge gap, we conducted a case study on the rapidly growing Research Triangle, North Carolina (USA) region, which has proposed to build a Light Railway by 2026 along a heavily used transportation corridor between the cities of Durham and Chapel Hill. At the same time, Durham County has set a goal of lowering greenhouse gas emissions by 30% from a 2005 baseline by 2030. In collaboration with local stakeholders, we developed a system dynamics model to simulate how Light Rail transit and concurrent policies could help or hinder these sustainable growth goals. The Durham–Orange Light Rail Project (D–O LRP) model simulates urban–regional dynamics between 2000 and 2040, including feedbacks from energy spending on economic growth and from land scarcity on development. Counter to expectations, model scenarios that included Light Rail had as much as 5% higher regional energy use and CO₂ emissions than business-as-usual (BAU) by 2040 despite many residents choosing to use public transit instead of private vehicles. This was largely due to an assumption that Light Rail increases demand for commercial development in the station areas, creating new jobs and attracting new residents. If regional solar capacity grew to 640 MW, this would offset the emissions growth, mostly from new buildings, that is indirectly due to Light Rail. National trends in building and automobile energy efficiency, as well as federal emissions regulation under the Clean Power Plan, would also allow significant progress toward the 2030 Durham emissions reduction goal. By simulating the magnitude of technology and policy effects, the D–O LRP model can enable policy makers to make strategic choices about regional growth.     

Physicochemical and microbiological quality of water from a pilot domestic rainwater harvesting facility in Ireland

Dublin Institute of Technology personnel were commissioned in 2005 by the Department of Environment, Heritage and Local Government in Ireland to assess the feasibility of utilizing harvested rainwater to replace treated mains water, for nonpotable uses. A pilot project was set up. The project involved the design, installation, commissioning and monitoring of rainwater harvesting facilities in a rural housing development. A monitoring programme was carried out to examine the physicochemical and microbiological quality of the harvested rainwater. Harvested rainwater was sampled monthly and tested. Analysis of the harvested rainwater quality showed a consistently high quality of raw water in general compliance with the requirements of the European Communities (Quality of Bathing Water) Regulations for 100% of samples and the European Communities (Drinking Water) Regulations, 2007 for 37% of sampling dates.     

Mobile Ferroelastic Domain Walls in Nanocrystalline PZT Films: the Direct Piezoelectric Effect

Ferroelastic (90°) domain wall motion occurs readily in bulk samples of displacive ferroelectrics such as Pb(Zr,Ti)O₃ (PZT), dictating critical piezoelectric, dielectric, and polarization switching properties. Many prior studies have used converse piezoelectric measurements to probe the dynamics of ferroelastic domains in thin films; however, such experiments are strongly influenced by the mechanical clamping effect of the substrate, which inhibits electric field‐induced 90° domain wall motion. Nevertheless, these observations raise a tantalizing question: Does the application of mechanical stress, rather than electric field, result in an entirely different response in thin films? Here we report biaxial stress‐driven crystallographic reorientation of (100)/(001) textured, 70 nm thick Pb(Zr_0.25Ti_0.75)O₃ films via 90° domain wall motion, measured in situ by both x‐ray diffraction and piezoforce microscopy. Visual evidence of nanoscale mechanisms that underlie the direct piezoelectric effect is shown. Mobile 90° domain walls effect complete orientation switching in the grains in which they operate, without apparent wall pinning, indicating that bulk‐like ferroelastic behavior can extend to nanocrystalline films in the absence of substrate clamping.     

A Bayesian spatial econometric analysis of the 2010 UK General Election

The Conservative Party won the 2010 General Election in the United Kingdom, gaining the most votes and seats of any single party. Using Bayesian spatial econometric methods, we show that significant spatial dependence exists in Conservative voting behaviour and select the spatial Durbin model as the best model to explain this phenomenon. This paper examines these spatial effects as well as the effects of a range of economic, socio‐economic, and political variables. Perhaps the most interesting result is that incumbency has effects beyond an incumbent's own constituency.